Efficacy and safety of dienogest versus GnRH-a combined with dienogest therapy for adenomyosis

Efficacy and safety of dienogest versus GnRH-a combined with dienogest therapy for adenomyosis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Efficacy and safety of dienogest versus GnRH-a combined with dienogest therapy for adenomyosis Shu Zhu, Qiqin Wang, Jiafan Sun, Wei Xu, Huiyuan Zhang, Xianglian Wang, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3509174/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective To investigate the efficacy and safety of dienogest((DNG) monotherapy and gonadotropin-releasing hormone agonist (GnRH-a) combined with DNG sequential treatment for adenomyosis. Methods This is a retrospective study.157 patients with symptomatic adenomyosis from the first affiliated hospital of Nanjing Medical University were enrolled in the study. 61patients treated with DNG (2mg/day) alone(Group 1). 96 patients treated with DNG (2mg/day) after 3–6 injections of GnRH-a(Group 2). Results ( 1) The Visual analogue scale (VAS) for dysmenorrhea, serum carbohydrate antigen (CA-125) and CA19-9 levels significantly decreased in both groups compared with pre-treatment (P < 0.05). (2) The hemoglobin (Hb) level in both groups after treatment were significantly higher than pre-treatment (P < 0.05). (3) At 15–24 months of DNG treatment, uterine volume decreased significantly in Group2 compared to pre-treatment (P < 0.05), with no significant change in Group1. (4) Group 2 showed a higher rate of amenorrhea and a lower incidence of irregular spotting and breakthrough bleeding. (5) There were no significant changes in coagulation, hepatorenal function and breast tissue before and after treatment in both groups. Conclusion Both DNG monotherapy and GnRH-a + DNG sequential therapy significantly relieved dysmenorrhea, improved anemia, and reduced CA125 and CA19-9 levels in patients with symptomatic adenomyosis, with no adverse effects on coagulation, hepatorenal function and breast tissue. The sequential therapy is superior to DNG monotherapy in reducing uterine volume and lowering CA125 levels. Sequential therapy achieved better amenorrhea rate. Diffuse lesions and lesion involvement of the endometrium were the high-risk factors of heavy breakthrough bleeding during DNG treatment. Adenomyosis dienogest GnRH-a dysmenorrhea. Figures Figure 1 Introduction Adenomyosis is characterized by the abnormal development of endometrial glands and stroma within the myometrium. Two thirds of adenomyosis patients are symptomatic [ 1 ] . The most common complaints are dysmenorrhea, menorrhagia and infertility [ 1 ] . The treatment of adenomyosis focuses on symptom control. Many of the medical protocols that have been used successfully to treat endometriosis are now also being used off-label for adenomyosis, such as combined oral contraceptive (COC), levonorgestrel-releasing intrauterine system (LNG-IUS), gonadotropin-releasing hormone agonist (GnRH-a) and dienogest (DNG) [ 2 ] . DNG is a progestational 19-norsteroid with good tolerance, anti-androgenic activity, moderately reduced estrogen levels and minimal effects on salt, sugar and lipid metabolism [ 3 ] . Compared with COC, DNG is more effective in treating symptomatic adenomyosis [ 4 ] . Moreover, the incidence of adenomyosis is highest in patients aged 41 to 45 years old. Long-term use of COC in those patients concerns the risk of venous thrombosis [ 5 ] . The oversized uterus with adenomyosis faces the risk of LNG-IUS expulsion, even it has been pretreated with GnRH-a [ 6 ] . Furthermore, DNG is superior to LNG-IUS in terms of duration of uterine bleeding [ 7 , 8 ] . DNG was comparable with GnRH-a in relieving dysmenorrhea of adenomyosis without the severe hypoestrogenic side effects [ 9 ] . The hypoestrogenism caused by GnRH-a limits its long-term use in treating adenomyosis. At these times, DNG can be an alternative option for pharmacological interventions for symptomatic adenomyosis. In this study, we retrospectively observed the changes of dysmenorrhea, hemoglobin (Hb), serum cancer antigen 125 (CA125), cancer antigen 19 − 9 (CA19-9), hepatorenal function, coagulation, uterine bleeding pattern, uterine volume and breast in patients with adenomyosis before and after treatment with DNG alone and GnRH-a combined with DNG sequential therapy. We aimed to comparatively evaluate the efficacy and safety of these two regimens in treating adenomyosis. Methods This retrospective study was conducted on 157 patients of adenomyosis who were evaluated from December 2019 to March 2023 at the first affiliated hospital of Nanjing Medical University. All the patients were enrolled according to the following criteria: (1) age 18–50 years and premenopausal status; (2) adenomyosis was diagnosed by transvaginal/transrectal ultrasound or magnetic resonance imaging (MRI) [10]; (3) intolerable abnormal uterine bleeding or dysmenorrhea; (4) no history of hormone pretreatment except for GnRH-a. The following patients were excluded: (1) with allergies or contraindications to the drugs used in this study;(2) pregnant; (3) concomitant uterine fibroids with diameter > 2 cm; (4) moderate to severe hepatic and renal dysfunction༛(5) with the history of breast cancer, ovary cancer, thrombosis or depression. 61 patients were treated with DNG (Visanne, Bayer Pharma AG, Germany) alone at a dose of 2 mg daily without a break (group 1). 96 patients received 3–6 injections of goserelin acetate (3.6 mg/4 weeks, AstraZeneca UK Limited, England) or triptorelin acetate (3.75 mg/4 weeks, Ipsen pharma biotech, France) before taking DNG (group 2)). DNG administration was started 28–35 days after the last GnRH-a dose. The main study variables collected were as follows: (1) visual analog scale (VAS) for dysmenorrhea; (2) serum CA125 and CA19-9; (3) uterine bleeding pattern was assessed by patient’s complaints and hemoglobin(Hb); (4) coagulation function was assessed by plasma prothrombin time (PT), PT international normalized ratio (PT-INR), activated partial thromboplastin time (APTT), fibrinogen time (FIB), thrombin time (TT) and D-dimer (D-D); (5) hepatorenal function was estimated with serum alanine aminotransferase (ALT), serum urea nitrogen (BUN), blood creatinine (Cr); (6) uterine volume was measured with the formula for an ovoid (length×width×depth×0.5) by transvaginal ultrasound; (7) breast was evaluated using the breast imaging reporting and data system (BI-RADS) [11]; (8)uterine bleeding patterns were classified as amenorrhea, irregular spotting bleeding and heavy breakthrough bleeding (twice the normal menstrual volum). SPSS 26 software was used for statistical analysis. Measurements that conformed to a normal distribution were analyzed by Student's t-test or ANOVA, and those that did not meet to a normal distribution were compared by nonparametric tests. Values were expressed as means ± standard deviation or were specified for non-continuous variables, as medians and ranges. Statistical significance was considered when P < 0.05. Results Basal characteristics of patients treated with DNG alone and GnRH-a + DNG The basal clinical characteristics of 157 patients with adenomyosis were summarized in Table 1. In terms of age, body mass index (BMI), hepatorenal function and coagulation function, no significant differences were seen between the two groups. Regarding Hb level, dysmenorrhea VAS score, uterine volume and serum CA125 level, the patients in group 2 showed significantly higher levels than those of group 1(P < 0.05). Table1. The basic clinical characteristics of patients in DNG monotherapy and GnR H-a +DNG sequential therapy groups Category DNG (n=61) GnRH-a +DNG (n=96) T or Z-value P-value Age (years, P 25 -P 75 ) 40.00(35.50~44.00) 42.00(39.00~45.00) -1.866 0.062 Gravidity [number, M ( P25-P75 )] 2.00(1.00~3.00) 2.00(1.00~3.75) -1.772 0.076 Parity [number, M ( P25-P75 )] 1.00(1.00~1.00) 1.00(1.00~1.00) -0.102 0.919 Abortion [number, M ( P25-P75 )] 1.00(0.00~2.00) 1.00(0.00~2.00) -1.666 0.096 BMI [Kg/m², M ( P25-P75 )] 22.27(20.57~23.49) 22.95(21.12~24.37) -1.509 0.131 Hb [g/L, M ( P25-P75 )] 120.00(99.00~136.00) 104.00(91.00~128.75) -2.136 0.033* PLT [*109/L, M ( P25-P75 )] 238.00(217.00~279.50) 256.00(214.25~291.50) -0.920 0.357 VAS [mm, M ( P25-P75 )] 70.00(70.00~80.00) 80.00(72.50~80.00) -4.260 <0.001* Uterine volume [cm 3 , M ( P25-P75 )] 180.17(133.82~236.00) 245.79(185.25~322.47) -4.453 <0.001* CA125 [U/mL, M ( P25-P75 )] 47.88(37.20~73.00) 143.10(109.08~182.48) -7.885 <0.001* CA19-9 [U/mL, M ( P25-P75 )] 20.35(17.89~31.98) 19.68(12.66~41.34) -0.223 0.823 PT [s, M ( P25-P75 )] 11.10(10.45~11.65) 10.90(10.50~11.78) -0.195 0.846 PT-INR [ M ( P25-P75 )] 0.96(0.93~1.03) 0.96(0.93~1.01) -0.674 0.500 APTT [s, ` x ±s ] 26.54±2.43 26.40±2.34 0.342 0.732 FIB [g/L, M ( P25-P75 )] 2.48(2.25~3.19) 2.53(2.32~3.09) -0.389 0.697 TT [s, M ( P25-P75 )] 17.30(16.90~17.60) 17.20(16.93~17.80) -0.060 0.953 D-D [mg/L, M ( P25-P75 )] 0.21(0.15~0.34) 0.20(0.15~0.30) -1.123 0.262 ALT [U/L, M ( P25-P75 )] 14.40(11.65~23.95) 13.85(10.80~17.10) -1.532 0.125 BUN [mmol/L, M ( P25-P75 )] 4.46(3.52~5.31) 4.40(3.50~5.80) -0.555 0.579 Cr [μmol/L, M ( P25-P75 )] 54.60(51.20~59.40) 54.10(52.13~60.40) -0.083 0.934 Abbreviation: BMI, body mass index; Hb, hemoglobin; PLT, platelet count; VAS, visual analogue pain score; CA125, carbohydrate antigen 125; CA19-9, carbohydrate antigen 19-9; PT, prothrombin time; PT-INR, international normalized ratio of prothrombin time; APTT, activated partial thromboplastin time; FIB, fibrinogen quantification; TT, thrombin time; D-D, D-dimer; ALT, alanine aminotransferase; BUN, serum urea nitrogen; Cr, creatinine. *P< 0.05. Loss of follow-up and discontinuation of medication Overall, 52/61 patients (85.2%) in the group 1 and 83/96 patients (86.5%) in the group 2 completed the 15-months follow-up. The rates of follow-up loss at this study were 6.6% (4/61) and 6.3% (6/96) in group 1 and group 2 respectively, without significant difference between groups (P = 1.00). The efficacy of DNG alone and GnRH-a + DNG treatment in adenomyosis The dysmenorrhea VAS scores, Hb levels, serum CA125 and CA19-9 levels as well as uterine volume pre and post treatment in both groups were presented in Table 2 . Both DNG alone and GnRH-a combined with DNG sequential therapy were significantly effective in controlling dysmenorrhea of adenomyosis, improveing anemia, and reduced CA125 and CA-19-9. Table 2 The efficacy of DNG monotherapy and GnRH-a + DNG sequential therapy in treating adenomyosis DNG items Baseline 3–6 months 9–12 months 15–24 months Number of patients 61 61 54 52 VAS [mm, M ( P25-P75 )] value 70.00(70.00–80.00) - 00.00(00.00–20.00) 00.00(00.00–00.00) 00.00(00.00–0.00) T or Z-value - -9.685 -9.353 -9.677 P value - < 0.001* < 0.001* < 0.001* Hb [g/L, M ( P25-P75 )] value 120.00(99.00-136.00) - 137.00(124.00-143.50) 138.00(124.75–142.00) 137.00(124.00-143.50) T or Z-value - -4.889 -4.574 -4.281 P value - < 0.001* < 0.001* < 0.001* CA125 [U/mL, M ( P25-P75 )] value 47.88(37.20–73.00) - 37.00(22.75–56.65) 23.70(15.50-36.38) 20.00(12.54–35.40) T or Z-value - -2.937 -6.381 -6.646 P value - 0.003* < 0.001* < 0.001* CA19-9 [U/mL, M ( P25-P75 )] value 20.35(17.89–31.98) - 16.27(10.87–20.65) 13.61(8.54–20.29) 15.03(6.25–18.08) T or Z-value - -3.526 -4.626 -5.554 P value - < 0.001* < 0.001* < 0.001* Uterine volume [cm 3 , M ( P25-P75 )] value 180.17(133.82–236.00) - 168.04(130.49-218.14) 155.88(115.83-216.06) 166.55(116.56-204.53) T or Z-value - -0.494 -1.622 -1.550 P value - 0.621 0.105 0.121 GnRH-a + DNG Baseline GnRH-a 3–6 injections 3–6 months 9–12 months 15–24 months Number of patients 96 96 96 87 83 VAS [mm, M ( P25-P75 )] value 80.00(72.50–80.00) 00.00(00.00–00.00) 00.00(00.00–00.00) 00.00(00.00–00.00) 00.00(00.00–00.00) T or Z-value - -12.855 -12.586 -12.230 -12.166 P value - < 0.001* < 0.001* < 0.001* < 0.001* Hb [g/L, M ( P25-P75 )] value 104.00(91.00-128.75) 132.50(126.00-140.75) 134.50(125.25-143.75) 134.00(121.00-142.00) 130.00(123.00-140.00) T or Z-value - -7.345 -7.413 -6.656 -5.307 P value - < 0.001* < 0.001* < 0.001* < 0.001* CA125 [U/mL, M ( P25-P75 )] value 143.10(109.08-182.48) 32.10(13.93–71.68) 21.50(14.33–47.08) 21.10(15.50–26.90) 20.00(17.20-26.66) T or Z-value - -9.905 -9.898 -10.809 -11.067 P value - < 0.001* < 0.001* < 0.001* < 0.001* CA19-9 [U/mL, M ( P25-P75 )] value 19.68(12.66–41.34) 17.05(8.35–24.59) 9.69(7.09–18.32) 12.35(6.48–19.10) 10.97(6.49–18.61) T or Z-value - -3.251 -5.939 -5.019 -5.623 P value - 0.001* < 0.001* < 0.001* < 0.001* Uterine volume [cm 3 , M ( P25-P75 )] value 245.79(185.25-322.47) 136.25(102.62–190.20) 240.47(166.61–323.40) 242.86(165.63-305.07) 212.94(156.45-259.39) T or Z-value - -7.727 -0.790 -1.020 -2.002 P value - < 0.001* 0.430 0.308 0.003* Abbreviation: VAS, visual analogue pain score; Hb, hemoglobin; CA125, carbohydrate antigen 125; CA19-9, carbohydrate antigen 19 − 9. *Compared to pre-treatment, P < 0.05. P-values 0.05). In group 2, uterine volume shrunk significantly after 3–6 injections of GnRH-a from 245.79(185.25 ~ 322.47) cm 3 to 136.25(102.62 ~ 190.20) cm 3 (P < 0.001). During the sequential treatment with DNG, the uterine volume rebound to 97.84%, 98.81%, and 86.63% of pre-treatment level at 3–6, 9–12 and 15–24 months respectively. The safety of DNG alone and GnRH-a + DNG treatment in adenomyosis The coagulation function and hepatorenal function showed no significant difference in all patients in both groups (P > 0.05) (Table 3 ). In terms of bleeding patterns during treatment, patients in the two groups showed variable presentations (Fig. 1 ). Table 3 The safety of DNG monotherapy and GnRH-a + DNG sequential therapy in treating adenomyosis DNG Items Baseline 3–6 months 9–12 months 15–24 months Number of patients 61 61 54 52 PT [s, M ( P25-P75 )] value 11.10(10.45–11.65) - 11.10(10.50–11.70) 11.30(10.70–11.90) 11.25(10.80–12.00) T or Z-value - -0.297 -1.935 -1.846 P value - 0.766 0.053 0.063 PT-INR [ M ( P25-P75 )] value 0.96(0.93–1.03) - 1.00(0.95–1.06) 0.99(0.94–1.03) 0.99(0.93–1.04) T or Z-value - -1.814 -1.013 -1.243 P value - 0.070* 0.311 0.214 APTT [s, ‾ x ± s ] value 26.54 ± 2.43 26.55 ± 2.2 26.41 ± 2.5 27.53 ± 2.43 T or Z-value - -0.021 0.269 -1.404 P value - 0.983 0.788 0.163 FIB [g/L, M ( P25-P75 )] value 2.48(2.25–3.19) 2.53(2.28–3.06) 2.62(2.29–3.09) 2.59(2.26–3.26) T or Z-value - -0.172 -0.261 -0.245 P value - 0.864 0.794 0.807 TT [s, M ( P25-P75 )] value 17.30(16.90–17.60) 17.00(16.30-17.65) 17.25(16.30-17.53) 17.10(16.70–17.40) T or Z-value - -1.811 -1.433 -1.807 P value - 0.070 0.152 0.071 D-D [mg/L, M ( P25-P75 )] value 0.21(0.15–0.34) 0.21(0.14–0.32) 0.18(0.13–0.34) 0.21(0.14–0.32) T or Z-value - -0.666 -0.917 -0.369 P value - 0.505 0.359 0.712 ALT [U/L, M ( P25-P75 )] value 14.40(11.65–23.95) 13.20(10.20–17.70) 15.25(10.95–22.63) 14.50(10.90–19.40) T or Z-value - -1.488 -0.120 -0.599 P value - 0.137 0.904 0.549 PLT [*109/L, M ( P25-P75 )] value 238.00(217.00-279.50) 241.00(200.50-287.50) 241.50(203.50-284.50) 233.00(216.50–286.00) T or Z-value - -0.187 -0.734 -0.063 P value - 0.852 0.463 0.949 BUN [mmol/L, M ( P25-P75 )] value 4.46(3.52–5.31) 4.00(3.58–5.09) 4.00(3.40–4.95) 4.30(3.50–5.20) T or Z-value - -0.791 -1.071 -0.105 P value - 0.429 0.284 0.916 Cr [µmol/L, M ( P25-P75 )] value 54.60(51.20–59.40) 58.30(51.10–64.90) 54.55(52.10–61.90) 58.60(52.00-60.80) T or Z-value - -1.931 -0.423 -1.924 P value - 0.054 0.672 0.054 GnRH-a + DNG Baseline GnRH-a 3–6 injections 3–6 months 9–12 months 15–24 months Number of patients 96 96 96 87 83 PT [s, M ( P25-P75 )] value 10.90(10.50-11.78) 11.20(10.45–11.80) 11.00(10.60-11.68) 11.00(10.60–11.50) 11.00(10.60–11.50) T or Z-value - -0.499 -0.601 -0.155 -0.113 P value - 0.618 0.548 0.877 0.910 PT-INR [ M ( P25-P75 )] value 0.96(0.93–1.01) 0.96(0.90–1.02) 0.98(0.93–1.02) 0.96(0.93-1.00) 0.96(0.92-1.00) T or Z-value - -0.293 -1.283 -0.150 -0.258 P value - 0.770 0.199 0.881 0.797 APTT [s, ‾ x ± s ] value 26.40 ± 2.34 26.37 ± 2.36 26.31 ± 2.18 26.56 ± 2.86 26.40 ± 2.34 T or Z-value - 0.106 0.292 -0.417 -1.292 P value - 0.916 0.771 0.677 0.198 FIB [g/L, M ( P25-P75 )] value 2.53(2.32–3.09) 2.59(2.24–2.85) 2.68(2.41-3.00) 2.57(2.33–2.83) 2.47(2.08–2.82) T or Z-value - -0.479 -1.423 -0.366 -1.921 P value - 0.632 0.155 0.714 0.055 TT [s, M ( P25-P75 )] value 17.20(16.93–17.80) 17.30(16.93–17.78) 17.15(16.63–17.70) 17.10(16.80–17.70) 17.10(16.80–17.60) T or Z-value - -0.212 -1.536 -1.402 -1.926 P value - 0.832 0.125 0.161 0.054 D-D [mg/L, M ( P25-P75 )] value 0.20(0.15–0.30) 0.21(0.15–0.31) 0.19(0.14–0.27) 0.21(0.14–0.29) 0.18(0.13–0.33) T or Z-value - -0.919 -0.620 -0.547 -0.003 P value - 0.358 0.535 0.585 0.998 ALT [U/L, M ( P25-P75 )] value 13.85(10.80–17.10) 12.95(10.50-17.38) 13.75(10.55–18.60) 14.30(11.40–19.10) 14.20(10.60–20.60) T or Z-value - -0.084 -0.542 -1.585 -1.141 P value - 0.933 0.588 0.113 0.254 PLT [*109/L, M ( P25-P75 )] value 256.00(214.25–291.50) 246.00(210.00-290.50) 236.50(215.50-280.50) 246.00(200.00-281.00) 244.00(214.00-285.00) T or Z-value - -0.594 -1.218 -1.480 -0.683 P value - 0.553 0.223 0.139 0.495 BUN [mmol/L, M ( P25-P75 )] value 4.40(3.50–5.80) 4.50(3.60–5.57) 4.40(3.53–5.29) 4.50(3.60–5.50) 4.66(3.70–5.70) T or Z-value - -0.256 -0.287 -0.020 -0.710 P value - 0.798 0.774 0.984 0.478 Cr [µmol/L, M ( P25-P75 )] value 54.10(52.13–60.40) 53.25(49.50–58.60) 53.85(48.95–60.60) 54.30(49.20–59.30) 53.90(50.30–58.30) T or Z-value - -1.667 -1.086 -1.083 -1.027 P value - 0.096 0.278 0.279 0.304 Abbreviation: PT, prothrombin time; PT-INR, international normalized ratio of prothrombin time; APTT, activated partial thromboplastin time; FIB, fibrinogen quantification; TT, thrombin time; D-D, D-dimer; ALT, alanine aminotransferase; BUN, serum urea nitrogen; Cr, creatinine. * Compared to pre-treatment, P 6 months were 40.98% (25/61), 66.67% (38/57) and 77.78% (42/54) respectively. The incidence of irregular spotting bleeding was 52.46% (32/61), 33.33% (19/57) and 22.22% (12/54), respectively. It is noteworthy that four patients (4/61,6.56%) experienced a heavy breakthrough bleeding during 1–3 months of DNG alone. For two of these patients, the DNG dose was increased to 3–4 mg/day for 7 days and then continued at 2 mg/day maintenance without unpredictable breakthrough bleeding during the next maintenance therapy. However, two other patients had poor efficacy after 7 days of treatment with 4 mg/day, which led them to switch to GnRH-a 3–6 injections followed by a DNG maintenance regimen. In group 2, at the 1–3 months, 4–6 months and > 6 months of sequential DNG treatment, the amenorrhea rate was 68.75% (66/96), 66.30% (61/92) and 70.45% (62/88) respectively. The incidence of irregular spotting bleeding was 31.25% (30/96), 33.70% (31/92) and 26.14% (23/88) respectively. Three patients (3/88,3.41%) experienced breakthrough bleeding at 6 ,6 and 24 months of sequential DNG treatment respectively. Two of the three patients were restarted with GnRH-a 3–6 injections followed by DNG treatment. Another patient underwent diagnostic curettage for thickened endometrium and postoperative pathology revealed a secretory stage endometrium. Unfortunately, this patient was subsequently lost to follow-up. Whether treated with DNG alone or GnRH-a combined with DNG sequentially, we did not observe any significant abnormal lesions in the patients' breast tissue during the follow-up period (Table 4 ), but a few patients showed variation in the size and location of their breast nodules. After consultation with the breast specialist, all of these patients had no indication for surgery and were advised to have the breast ultrasound every 3 months while taking DNG. Table 4 The impact of DNG monotherapy and GnRH-a + DNG sequential therapy on breast tissue DNG GnRH-a + DNG Pre-treatment 3–6 months 9–12 months 15–24 months Pre-treatment 3–6 months 9–12 months 15–24 months Nodule free 33 32((-1)) 32 30(-2) 56 55(-1) 54(-1) 54 Unilateral BI-RADS 1 1 1 1 1 1 1 1 1 BI-RADS 2 2 2 2 2 1 1 1 1 BI-RADS 3 10 10 9(-1) 4 9 8(-1) 8 8 Bilateral BI-RADS 1 1 1 1 1 1 1 1 1 BI-RADS 2 0 0 0 0 3 3 3 2(-1) BI-RADS 3 10 11(+ 1) 12(+ 1) 14(+ 2) 15 17(+ 2) 18(+ 1) 19(+ 1) Total 57 86 Discussion 1. The efficacy of DNG alone and GnRH-a + DNG on dysmenorrhea. Many studies have demonstrated the benefit of DNG in relieving the dysmenorrhea symptoms of adenomyosis [ 9 , 12 – 15 ] . To the long-term efficacy of DNG on adenomyosis, Osuga Y et al reported that the mean VAS values decreased 56.7 ± 24.2 mm at 52 weeks of DNG treatment [ 14 ] . Neriishi K et al even noted that DNG has a remarkable pain relief effect continued up to menopause or for a long period of > 80 months [ 15 ] . Matsushima T et al reported that after 6 months of GnRH-a or DNG, all patients’ subjective symptoms disappeared. But symptoms recurred rapidly in the first six months after discontinuation of GnRH-a treatment [ 16 ] . In our study, patients exhibited a higher complete relief of dysmenorrhea after 3–6 injections of GnRH-a than 3–6 months of DNG alone. From 9–12 months, the complete pain relief rate was comparable in both groups. This suggests that long-term (≥ 12 months) treatment with DNG alone or sequential treatment with DNG after GnRH-a is comparable in controlling adenomyosis-related dysmenorrhea. The effect of DNG alone and GnRH-a + DNG on serum CA125 and CA19-9 Itagaki H et al found that the serum CA125 level correlated positively with the weight of adenomyosis and it is an important indicator for evaluating recurrence [ 1 7] . Kil K et al. even proposed that the cut-off value of 19 U/mL for serum CA125 provides a better differentiation between adenomyosis and myomas [ 18 ] . In studies assessing the efficacy of DNG on symptomatic adenomyosis, serum CA125 was also an important evaluator. Hirata T et al found that the serum CA125 significantly decreased from 150.6 ± 136.4 U/mL (baseline) to 69.5 ± 88.4 U/mL at 24 weeks of DNG treatment [ 13 ] . Neriishi K et al. observed a significant decrease in serum CA125 from 124.1 ± 84.0 to 19.6 ± 6.7 IU/ml with long-term DNG administration (> 80 months) [ 15 ] . Matsushima T et al noted that after 16 weeks of treatment, the effect of DNG in lowering serum CA125 can be comparable to that of GnRH-a and lowdose estrogenprogestin combination [19] . In our study, CA125 levels decreased by 22.72%, 50.50% and 58.23% after 3–6, 9–12 and 15–24 months of treatment with DNG alone, respectively. In group 2, CA125 levels dropped by 77.62% after 3–6 injections of GnRH-a. After 3–6, 9–12, and 15–24 months of subsequent maintenance treatment with DNG, CA125 levels declined by 85.07%, 85.29%, and 86.02%, respectively. This suggests that GnRH-a + DNG sequencing therapy is superior to DNG monotherapy in lowering CA125 levels. The effect of DNG alone and GnRH-a + DNG on uterine volume Regarding the effect of DNG on uterine volume of adenomyosis, the current studies were inconsistent. Fawzy et al. observed that uterine volume decreased by 12.27% (P > 0.05) after 16 weeks of treatment with DNG [ 20 ] . Hirata et al. showed that uterine volume decreased by 8.97% (P > 0.05) in patients treated with DNG for 6 months [ 13 ] . Osuga Y et al. found that the mean reduction in uterine size was 20.6 ± 30.3% at 24 weeks and 26.0 ± 27.9% at 52 weeks of DNG treatment [ 14 ] . Neriishi K et al. discovered that long-term DNG administration (> 80 months) resulted in a significant 30.49% reduction (P < 0.01) in uterine size [ 15 ] . Hassanin AI et al observed that uterine volume decreased 31.57% (P 0.05) respectively when treated with DNG and COCs for 6 months [ 4 ] . Similar decreases were observed in the diffuse and focal subtypes of adenomyosis treated with DNG at 12 to 24 months [ 8 ] . Nevertheless, Ji et al. found that uterine volume increased by 15.33% (P > 0.05) after 12 weeks of treatment with DNG [ 9 ] . Matsushima T et al reported that after treated with DNG for 16 weeks, the uterine volume increased 12.68% [ 19 ] . Their team also noticed that the uterine volume decreased by 54.25% after 6 injections with GnRH-a and rebounded to 82.79% of the pre-treatment volume after 6 months of discontinuation. When DNG was supplemented for 6 months after discontinuing GnRH-a, the uterine volume was 72.24% of the pre-treatment level [ 16 ] . In our study, when treated with DNG alone, the uterine volume decreased 6.73%, 13.48% and 7.56% at 3–6, 9–12 and 15–24 months respectively (P > 0.05). In group 2, uterine volume shrunk 44.57% (P < 0.05) after 3–6 injections GnRH-a and then rebound to 97.84%, 98.81%, and 86.63% of pre-treatment level at 3–6, 9–12 and 15–24 months of sequential DNG treatment. At the endpoint of this study (15–24 months), GnRH-a combined with DNG sequential therapy was superior to DNG monotherapy in reducing uterine volume. The effect of DNG alone and GnRH-a + DNG on hemoglobin and uterine bleeding pattern. Menorrhagia and anemia are the common clinical manifestations in patients with adenomyosis. It has been observed that the Hb increased from 11.6 ± 1.5 mg/dL to 12.3 ± 2.0 mg/dL at 24 weeks of DNG treatment [ 13 ] . Osuga Y et al. reported that DNG treatment caused an improvement of Hb from 12.8 ± 1.2 g/dL to 13.5 ± 0.9 g/dL (24 weeks) and 13.5 ± 0.9 g/dL (52 weeks) [ 14 ] . Matsushima T et al found that the elevated levels of Hb were comparable between patients treated with GnRH-a and DNG for 6 months. [ 16 ] . Hassanin et al. also observed that the improvement of Hb in patients taking DNG for 6 months was comparable to that of patients taking COC for 6 months [ 4 ] . Our study also showed that either DNG alone or GnRH-a followed by DNG significantly increased Hb levels and improved anemia symptoms. (P < 0.05). Irregular uterine bleeding is a common symptom experienced by women treated with DNG, especially in the first 3 months of treatment. Fortunately, as treatment continues, the length and intensity of uterine bleeding decreases [ 21 ] . Uterine bleeding induced by DNG was more likely to occur in subjects with adenomyosis than in those with endometriosis alone [ 22 ] . In endometriosis, the number of discontinuations due to heavy or irregular bleeding was low (2/332) [ 23 ] . However, in adenomyosis, the number of these patients increased greatly. Nagata C et al. reported that 36 of 51 patients (70.6%) continued DNG treatment for more than 12 months, and 8 (15.7%) patients discontinued treatment due to uterine bleeding. High risk factors for discontinuation of DNG treatment included age < 38 years, Hb < 12 g/L prior to treatment, and estradiol ≥ 60 pg/ml at the third month of treatment [ 24 ] . Matsubara S et al. found that 14 of 37 patients (37.8%) with symptomatic adenomyosis experienced severe unpredictable bleeding during DNG treatment that was associated with subtype I (intrinsic) adenomyosis [ 25 ] . Neriishi K et al. discovered that 22.2% (4/18) of patients stopped DNG therapy because of severe metrorrhagia and the mean duration of DNG treatment was 7.0 ± 3.5 months. Compared with patients taking DNG continuously, the dysmenorrhea VAS score and serum CA125 level at baseline were significantly increased and the basal Hb level and the frequency of subtype II (extrinsic) were significantly decreased in the cases of discontinuation [ 15 ] . Ono N et al observed that 35% (7/20) of women discontinued DNG within 12 months due to unbearable metrorrhagia. The uterus size was significantly larger and anterior wall lesions were more common in the discontinued group than in the continued group. They proposed that patients with uterine major axis of less than 9 cm, minor axis of 6 cm, maximum myometrial thickness of 4cm, and uterine body length of 4.5cm could tolerate DNG treatment [ 26 ] . In our study, pretreatment with GnRH-a achieved better amenorrhea rates and lower spotting bleeding rate. However, both groups had cases of heavy breakthrough bleeding during treatment, that is, four patients (4/61,6.56%) in group 1 and three cases (3/88,3.41%) in group 2. The clinical characteristics of these patients were analyzed retrospectively. 6 patients (6/7, 85.71%) had diffuse adenomyosis lesions, 5 patients (5/7, 71.43%) showed lesions compressing the endometrium, and 5 patients (5/7, 71.43%) had hemoglobin < 105 g/L before treatment. Regarding the CA125 level, three patients (3/4,75.00%) treated with group 1 and two patients (2/3, 66.67%) in group 2 were above the average level within the group. As to the management of unpredictable bleeding during DNG treatment, a 5 ~ 7-day break of DNG, DNG dose increased from 2 mg to 4 mg daily for 5–7 days or a short-term application of 1 mg estradiol have been described as valid approaches to interrupt the uterine bleeding [ 27 – 29 ] . Another option was to treat with GnRH-a to achieve amenorrhea and then switch to DNG [ 30 ] . In this study, two patients in the group 1 increased to 3–4 mg/day for 7 days and then continued at 2 mg/day maintenance without unpredictable breakthrough bleeding during the next follow-up. Another two patients in group 1 were switched to GnRH-a injection followed by DNG because of poor efficacy after double-dose treatment with DNG. Two patients in group 2 were re-injected with GnRH-a followed by DNG. The safety of DNG Overall, DNG was a well-tolerated treatment for symptomatic adenomyosis with a good safety for long-term use. It had no adverse effects on hepatorenal and coagulation function during the treatment. As to the effect of DNG on breast, four randomized clinical trials of 2 mg DNG treatment in 332 women with endometriosis, 18 (5.4%) women reported breast discomfort, including 11 cases of breast tenderness, 4 cases of breast swelling, and 3 cases of breast pain [ 23 ] . In this study, A few patients showed variations in the size and location of breast nodules. But none of the breast nodules progressed to BI-RADS 4 lesions. More cases and longer time are required to further evaluate the effect of DNG on breast. Conclusion Overall, our study confirmed the efficacy and good tolerability of long-term DNG use in symptomatic adenomyosis. GnRH-a combined with DNG sequential therapy was superior to DNG monotherapy in reducing uterine volume, lowering CA125 level, achieving higher amenorrhea rate and lower spotting bleeding rate. Diffuse lesions, and lesion involvement of the endometrium were the high-risk factors of heavy breakthrough bleeding during DNG treatment. The effect of DNG on the breast needs more cases and more time to be further evaluated. However, as a single-center retrospective study, this study inevitably had many limitations. For example, the subjective bias of clinicians in the selection of treatment regimens and the different adenomyosis characteristics at baseline of the two groups. Multicenter, randomized and double-blind prospective are needed to further clarify the efficacy and safety of DNG monotherapy and GnRH-a combined with DNG sequencing therapy on symptomatic adenomyosis. Declarations Author Contributions Xiuli Wang: study conception and design, data validation, data analysis and manuscript revision. Shu Zhu: data review, statistics and analysis, manuscript writing. Qiqin Wang: Data collections, statistics and analysis. Jiafan Sun: patient follow-up, data collection Wei Xu: data review, statistics and analysis, partial manuscript writing. Huiyuan Zhang: patient follow-up, data collection. Xianglian Wang: data statistical analysis. Wennian Yu: patient follow-up, data collection. Funding The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. Conflict of interest The authors have no conflicts of interest to declare that are relevant to the content of this article. Ethical approval The study was approved by the Medical Ethics Committee of Jiangsu Province Hospital (2023-SR-070). Informed consent Written informed consents were obtained from all participants before the study. Informed consent Informed consent was obtained from all individual participants included in the study. References Bourdon M, Santulli P, Marcellin L, Maignien C, Maitrot-Mantelet L, Bordonne C (2021) Adenomyosis: An update regarding its diagnosis and clinical features. Gynecol Obstet Hum Reprod 50:102228. https://doi.org/10.1016/j.jogoh.2021.102228 Schrager S, Yogendran L, Marquez CM, Sadowski EA (2022) Adenomyosis: Diagnosis and Management. Am Fam Physician 105(1):33–38 Ferrero S, Remorgida V, Venturini PL, Bizzarri N (2015) Endometriosis: the effffects of dienogest. BMJ Clin Evid 2015:0802 Hassanin AI, Youssef AA, Yousef AM, Ali MK (2021) Comparison of dienogest versus combined oral contraceptive pills in the treatment of women with adenomyosis: A randomized clinical trial. Int J Gynaecol Obstet 154:263–269. https://doi.org/10.1002/ijgo.13600 Khialani D, Rosendaal F, Vlieg AVH (2020) Hormonal Contraceptives and the Risk of Venous Thrombosis. Semin Thromb Hemost 46:865–871. https://doi.org/10.1055/s-0040-1715793 Youm J, Lee HJ, Kim SK, Kim H, Jee BC (2014) Factors affecting the spontaneous expulsion of the levonorgestrel-releasing intrauterine system. Int J Gynaecol Obstet 126:165–169. https://doi.org/10.1016/j.ijgo.2014.02.017 Ota I, Taniguchi F, Ota Y, Nagata H, Wada I, Nakaso T (2021) A controlled clinical trial comparing potent progestins, LNG-IUS and dienogest, for the treatment of women with adenomyosis. Reprod Med Biol 20:427–434. https://doi.org/10.1002/rmb2.12408 Yang S, Liu Y, Wen J, Sun Y, Ren F (2022) Clinical Efficacy of Dienogest versus Levonorgestrel-Releasing Intrauterine System for Adenomyosis. Evid Based Complement Alternat Med 2022:1995472. https://doi.org/10.1155/2022/1995472 Ji M, Yuan M, Jiao X, Li Q, Huang Y, Li J (2022) A cohort study of the efficacy of the dienogest and the gonadotropin-releasing hormone agonist in women with adenomyosis and dysmenorrhea. Gynecol Endocrinol 38:164–169. https://doi.org/10.1080/09513590.2021.2000961 Chapron C, Vannuccini S, Santulli P, Abrão MS, Carmona F, Fraser IS (2020) Diagnosing adenomyosis: an integrated clinical and imaging approach. Hum Reprod Update 26:392–411. https://doi.org/10.1093/humupd/dmz049 Spak DA, Plaxco JS, Santiago L, Dryden MJ, Dogan BE (2017) BI-RADS® fifth edition: A summary of changes. Diagn Interv Imaging 98:179–190. https://doi.org/10.1016/j.diii.2017.01.001 Osuga Y, Fujimoto Okabe H, Hagino A (2017) Evaluation of the efficacy and safety of dienogest in the treatment of painful symptoms in patients with adenomyosis: a randomized, double blind, multicenter, placebo controlled study. Fertil Steril 108:673678. https://doi.org/10.1016/j.fertnstert.2017.07.021 Hirata T, Izumi G, Takamura M, Saito A, Nakazawa A, Harada M, Hirota Y, Koga K, Fujii T, Osuga Y (2014) Efficacy of dienogest in the treatment of symptomatic adenomyosis: a pilot study. Gynecol Endocrinol 30:726–729. https://doi.org/10.3109/09513590.2014.926882 Osuga Y, Watanabe M, Hagino A (2017) Long term use of dienogest in the treatment of painful symptoms in adenomyosis. J Obstet Gynaecol Res 43:14411448. https://doi.org/10.1111/jog.13406 Neriishi K, Hirata T, Fukuda S, Izumi G, Nakazawa A, Yamamoto N (2018) Long-term dienogest administration in patients with symptomatic adenomyosis. J Obstet Gynaecol Res 44:1439–1444. https://doi.org/10.1111/jog.13674 Matsushima T, Akira S, Yoneyama K, Takeshita T (2020) Recurrence of uterine adenomyosis after administration of gonadotropin-releasing hormone agonist and the efficacy of dienogest. Gynecol Endocrinol 36:521–524. https://doi.org/10.1080/09513590.2019.1683818 Itagaki H, Nishida M, Kodaira Y, Sakanaka M, Ichikawa R, Arai Y (2022) Relationship between the serum cancer antigen 125 level and the weight of surgically enucleated adenomyosis. J Obstet Gynaecol 42(6):2064–2068. https://doi.org/10.1080/01443615.2022.2065906 Kil K, Chung JE, Pak HJ, Jeung IC, Kim JH, Jo HH (2015) Usefulness of CA125 in the differential diagnosis of uterine adenomyosis and myoma. Eur J Obstet Gynecol Reprod Biol 185:131–135. https://doi.org/10.1016/j.ejogrb.2014.12.008 Matsushima T, Akira S, Fukami T, Yoneyama K, Takeshita T (2018) Efficacy of Hormonal Therapies for Decreasing Uterine Volume in Patients with Adenomyosis. Gynecol Minim Invasive Ther 7:119–123. https://doi.org/10.4103/GMIT.GMIT_35_18 Fawzy M, Mesbah Y (2015) Comparison of dienogest versus triptorelin acetate in premenopausal women with adenomyosis: a prospective clinical trial. Arch Gynecol Obstet 292:1267–1271. https://doi.org/10.1007/s00404-015-3755-5 Yang S, Liu Y, Wen J, Sun Y, Ren F (2022) Clinical Efficacy of Dienogest versus Levonorgestrel-Releasing Intrauterine System for Adenomyosis. Evid Based Complement Alternat Med 2022:1995472. https://doi.org/10.1155/2022/1995472 Osuga Y, Hayashi K, Kanda S (2020) Long-term use of dienogest for the treatment of primary and secondary dysmenorrhea. J Obstet Gynaecol Res 46:606–617. https://doi.org/10.1111/jog.14209 Strowitzki T, Faustmann T, Gerlinger C, Schumacher U, Ahlers C, Seitz C (2015) Safety and tolerability of dienogest in endometriosis: pooled analysis from the European clinical study program. Int J Womens Health 7:393–401. https://doi.org/10.2147/IJWH.S77202 Nagata C, Yanagida S, Okamoto A, Morikawa A, Sugimoto K, Okamoto S (2012) Risk factors of treatment discontinuation due to uterine bleeding in adenomyosis patients treated with dienogest. J Obstet Gynaecol Res 38:639–644. https://doi.org/10.1111/j.1447-0756.2011.01778.x Matsubara S, Kawaguchi R, Akinishi M, Nagayasu M, Iwai K, Niiro E (2019) Subtype I (intrinsic) adenomyosis is an independent risk factor for dienogest-related serious unpredictable bleeding in patients with symptomatic adenomyosis. Sci Rep 9:17654. https://doi.org/10.1038/s41598-019-54096-z Ono N, Asano R, Nagai K, Sugo Y, Nakamura T, Miyagi E (2021) Evaluating the safety of dienogest in women with adenomyosis: A retrospective analysis. J Obstet Gynaecol Res 47:1433–1440. https://doi.org/10.1111/jog.14612 Römer T (2018) Long-term treatment of endometriosis with dienogest: retrospective analysis of efficacy and safety in clinical practice. Arch Gynecol Obstet 298:747–753. https://doi.org/10.1007/s00404-018-4864-8 Nirgianakis K, Vaineau C, Agliati L, McKinnon B, Gasparri ML, Mueller MD (2021) Risk factors for non-response and discontinuation of Dienogest in endometriosis patients: A cohort study. Acta Obstet Gynecol Scand 100:30–40. https://doi.org/10.1111/aogs.13969 Murji A, Biberoğlu K, Leng J, Mueller MD, Römer T, Vignali M (2020) Use of dienogest in endometriosis: a narrative literature review and expert commentary. Curr Med Res Opin 36:895–907. https://doi.org/10.1111/aogs.13969 Kitawaki J, Kusuki I, Yamanaka K, Suganuma I (2011) Maintenance therapy with dienogest following gonadotropin-releasing hormone agonist treatment for endometriosis-associated pelvic pain. Eur J Obstet Gynecol Reprod Biol 157:212–216. https://doi.org/10.1016/j.ejogrb.2011.03.012 Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3509174","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":252920543,"identity":"86d42ca4-c179-4c03-9de9-d04430b9070a","order_by":0,"name":"Shu Zhu","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Shu","middleName":"","lastName":"Zhu","suffix":""},{"id":252920544,"identity":"8a797946-1fb9-46e0-a51d-c11833f6e741","order_by":1,"name":"Qiqin Wang","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Qiqin","middleName":"","lastName":"Wang","suffix":""},{"id":252920545,"identity":"58bdbb88-7f9d-4ebb-9898-ca72f65f090c","order_by":2,"name":"Jiafan Sun","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Jiafan","middleName":"","lastName":"Sun","suffix":""},{"id":252920546,"identity":"9cc02bed-60ff-4cbd-8db0-6f783f9a82ad","order_by":3,"name":"Wei Xu","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Wei","middleName":"","lastName":"Xu","suffix":""},{"id":252920547,"identity":"7e31f5f6-d063-44af-9071-02f401798a3e","order_by":4,"name":"Huiyuan Zhang","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Huiyuan","middleName":"","lastName":"Zhang","suffix":""},{"id":252920548,"identity":"232a49d7-87cc-43f8-842a-9f66348b5a6e","order_by":5,"name":"Xianglian Wang","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Xianglian","middleName":"","lastName":"Wang","suffix":""},{"id":252920549,"identity":"594df092-69aa-4460-b913-9b3e9deea2a9","order_by":6,"name":"Wennian Yu","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Wennian","middleName":"","lastName":"Yu","suffix":""},{"id":252920550,"identity":"792599dc-8ed7-41f0-831a-9530307cae57","order_by":7,"name":"Xiuli Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0klEQVRIie3QMQrCMBSA4VeE1CGQTVIKeoUnHVToETxEujg5eAOFroqrooeoN4g8cBNXwUXxAhk7qUHB0WR0yL/kDfmG9wBCoT8MCSKtIG+LuNTa1H4ELBllyfxQ7NdzD5LMLAGgoloNM2oyDyJijvoKjaiS3BBw6IiW/k1YwxJln166qGjSh+56o7wIZ4PtsaIVB4UXBxEfIjmex1fizIMk5ZugtAT8CBKbWKLQHhntkaV7FzzR7lbDc7qMy7sxdd4RqYO8ix7fUXp8D4VCoZCzFxsTRoPTGtzjAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0001-8421-5559","institution":"The First Affiliated Hospital With Nanjing Medical University","correspondingAuthor":true,"prefix":"","firstName":"Xiuli","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2023-10-30 00:29:29","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3509174/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3509174/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":47309253,"identity":"b5d2305c-681d-4ada-9036-2a06b688b4bd","added_by":"auto","created_at":"2023-11-29 16:25:46","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":33089,"visible":true,"origin":"","legend":"\u003cp\u003eThe incidence of abnormal uterine bleeding in DNG monotherapy and GnRH-a+DNG sequential therapy groups.\u003c/p\u003e\n\u003cp\u003eAbnormal uterine bleeding includes amenorrhea, irregular spotting bleeding and heavy breakthrough bleeding\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-3509174/v1/2918e86c7704484b62374407.png"},{"id":49597836,"identity":"b0389069-782f-449c-bb39-84c6852062fa","added_by":"auto","created_at":"2024-01-15 03:19:44","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":659181,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3509174/v1/2d3caef1-6c87-4907-8d57-1624340f0a74.pdf"}],"financialInterests":"","formattedTitle":"Efficacy and safety of dienogest versus GnRH-a combined with dienogest therapy for adenomyosis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAdenomyosis is characterized by the abnormal development of endometrial glands and stroma within the myometrium. Two thirds of adenomyosis patients are symptomatic \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. The most common complaints are dysmenorrhea, menorrhagia and infertility \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. The treatment of adenomyosis focuses on symptom control. Many of the medical protocols that have been used successfully to treat endometriosis are now also being used off-label for adenomyosis, such as combined oral contraceptive (COC), levonorgestrel-releasing intrauterine system (LNG-IUS), gonadotropin-releasing hormone agonist (GnRH-a) and dienogest (DNG) \u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eDNG is a progestational 19-norsteroid with good tolerance, anti-androgenic activity, moderately reduced estrogen levels and minimal effects on salt, sugar and lipid metabolism \u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. Compared with COC, DNG is more effective in treating symptomatic adenomyosis \u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. Moreover, the incidence of adenomyosis is highest in patients aged 41 to 45 years old. Long-term use of COC in those patients concerns the risk of venous thrombosis \u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. The oversized uterus with adenomyosis faces the risk of LNG-IUS expulsion, even it has been pretreated with GnRH-a \u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. Furthermore, DNG is superior to LNG-IUS in terms of duration of uterine bleeding \u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e. DNG was comparable with GnRH-a in relieving dysmenorrhea of adenomyosis without the severe hypoestrogenic side effects \u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e. The hypoestrogenism caused by GnRH-a limits its long-term use in treating adenomyosis. At these times, DNG can be an alternative option for pharmacological interventions for symptomatic adenomyosis.\u003c/p\u003e \u003cp\u003eIn this study, we retrospectively observed the changes of dysmenorrhea, hemoglobin (Hb), serum cancer antigen 125 (CA125), cancer antigen 19\u0026thinsp;\u0026minus;\u0026thinsp;9 (CA19-9), hepatorenal function, coagulation, uterine bleeding pattern, uterine volume and breast in patients with adenomyosis before and after treatment with DNG alone and GnRH-a combined with DNG sequential therapy. We aimed to comparatively evaluate the efficacy and safety of these two regimens in treating adenomyosis.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThis retrospective study was conducted on 157 patients of adenomyosis who were evaluated from December 2019 to March 2023 at the first affiliated hospital of Nanjing Medical University. All the patients were enrolled according to the following criteria: (1) age 18\u0026ndash;50 years and premenopausal status; (2) adenomyosis was diagnosed by transvaginal/transrectal ultrasound or magnetic resonance imaging (MRI) [10]; (3) intolerable abnormal uterine bleeding or dysmenorrhea; (4) no history of hormone pretreatment except for GnRH-a. The following patients were excluded: (1) with allergies or contraindications to the drugs used in this study;(2) pregnant; (3) concomitant uterine fibroids with diameter\u0026thinsp;\u0026gt;\u0026thinsp;2 cm; (4) moderate to severe hepatic and renal dysfunction༛(5) with the history of breast cancer, ovary cancer, thrombosis or depression.\u003c/p\u003e \u003cp\u003e61 patients were treated with DNG (Visanne, Bayer Pharma AG, Germany) alone at a dose of 2 mg daily without a break (group 1). 96 patients received 3\u0026ndash;6 injections of goserelin acetate (3.6 mg/4 weeks, AstraZeneca UK Limited, England) or triptorelin acetate (3.75 mg/4 weeks, Ipsen pharma biotech, France) before taking DNG (group 2)). DNG administration was started 28\u0026ndash;35 days after the last GnRH-a dose.\u003c/p\u003e \u003cp\u003eThe main study variables collected were as follows: (1) visual analog scale (VAS) for dysmenorrhea; (2) serum CA125 and CA19-9; (3) uterine bleeding pattern was assessed by patient\u0026rsquo;s complaints and hemoglobin(Hb); (4) coagulation function was assessed by plasma prothrombin time (PT), PT international normalized ratio (PT-INR), activated partial thromboplastin time (APTT), fibrinogen time (FIB), thrombin time (TT) and D-dimer (D-D); (5) hepatorenal function was estimated with serum alanine aminotransferase (ALT), serum urea nitrogen (BUN), blood creatinine (Cr); (6) uterine volume was measured with the formula for an ovoid (length\u0026times;width\u0026times;depth\u0026times;0.5) by transvaginal ultrasound; (7) breast was evaluated using the breast imaging reporting and data system (BI-RADS) [11]; (8)uterine bleeding patterns were classified as amenorrhea, irregular spotting bleeding and heavy breakthrough bleeding (twice the normal menstrual volum).\u003c/p\u003e \u003cp\u003eSPSS 26 software was used for statistical analysis. Measurements that conformed to a normal distribution were analyzed by Student's t-test or ANOVA, and those that did not meet to a normal distribution were compared by nonparametric tests. Values were expressed as means\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation or were specified for non-continuous variables, as medians and ranges. Statistical significance was considered when P\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n\u003ch2\u003eBasal characteristics of patients treated with DNG alone and GnRH-a\u0026thinsp;+\u0026thinsp;DNG\u003c/h2\u003e\n\u003cp\u003eThe basal clinical characteristics of 157 patients with adenomyosis were summarized in Table\u0026nbsp;1. In terms of age, body mass index (BMI), hepatorenal function and coagulation function, no significant differences were seen between the two groups. Regarding Hb level, dysmenorrhea VAS score, uterine volume and serum CA125 level, the patients in group 2 showed significantly higher levels than those of group 1(P\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable1. \u003c/strong\u003e\u003cstrong\u003eThe basic clinical characteristics of patients in DNG monotherapy and GnR\u003c/strong\u003e\u003cstrong\u003eH-a +DNG\u003c/strong\u003e\u003cstrong\u003e sequential therapy\u003c/strong\u003e \u003cstrong\u003egroups\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" width=\"95%\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd width=\"29%\"\u003e\n\u003cp\u003e\u003cstrong\u003eCategory\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003e\u003cstrong\u003eDNG (n=61)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"28%\"\u003e\n\u003cp\u003e\u003cstrong\u003eGnRH-a +DNG (n=96)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\n\u003cp\u003e\u003cstrong\u003eT or Z-value\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\n\u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"29%\"\u003e\n\u003cp\u003eAge (years, P\u003csub\u003e25\u003c/sub\u003e-P\u003csub\u003e75\u003c/sub\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003e40.00(35.50~44.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"28%\"\u003e\n\u003cp\u003e42.00(39.00~45.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\n\u003cp\u003e-1.866\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\n\u003cp\u003e0.062\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"29%\"\u003e\n\u003cp\u003eGravidity [number, \u003cem\u003eM \u003c/em\u003e(\u003cem\u003eP25-P75\u003c/em\u003e)]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003e2.00(1.00~3.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"28%\"\u003e\n\u003cp\u003e2.00(1.00~3.75)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\n\u003cp\u003e-1.772\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\n\u003cp\u003e0.076\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"29%\"\u003e\n\u003cp\u003eParity [number, \u003cem\u003eM \u003c/em\u003e(\u003cem\u003eP25-P75\u003c/em\u003e)]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003e1.00(1.00~1.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"28%\"\u003e\n\u003cp\u003e1.00(1.00~1.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\n\u003cp\u003e-0.102\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\n\u003cp\u003e0.919\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"29%\"\u003e\n\u003cp\u003eAbortion [number, \u003cem\u003eM \u003c/em\u003e(\u003cem\u003eP25-P75\u003c/em\u003e)]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003e1.00(0.00~2.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"28%\"\u003e\n\u003cp\u003e1.00(0.00~2.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\n\u003cp\u003e-1.666\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\n\u003cp\u003e0.096\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"29%\"\u003e\n\u003cp\u003eBMI [Kg/m\u0026sup2;,\u003cem\u003e M \u003c/em\u003e(\u003cem\u003eP25-P75\u003c/em\u003e)]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003e22.27(20.57~23.49)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"28%\"\u003e\n\u003cp\u003e22.95(21.12~24.37)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\n\u003cp\u003e-1.509\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\n\u003cp\u003e0.131\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"29%\"\u003e\n\u003cp\u003eHb [g/L,\u003cem\u003e M \u003c/em\u003e(\u003cem\u003eP25-P75\u003c/em\u003e)]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003e120.00(99.00~136.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"28%\"\u003e\n\u003cp\u003e104.00(91.00~128.75)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\n\u003cp\u003e-2.136\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\n\u003cp\u003e0.033*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"29%\"\u003e\n\u003cp\u003ePLT [*109/L,\u003cem\u003e M \u003c/em\u003e(\u003cem\u003eP25-P75\u003c/em\u003e)]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003e238.00(217.00~279.50)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"28%\"\u003e\n\u003cp\u003e256.00(214.25~291.50)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\n\u003cp\u003e-0.920\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\n\u003cp\u003e0.357\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"29%\"\u003e\n\u003cp\u003eVAS [mm,\u003cem\u003e M \u003c/em\u003e(\u003cem\u003eP25-P75\u003c/em\u003e)]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003e70.00(70.00~80.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"28%\"\u003e\n\u003cp\u003e80.00(72.50~80.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\n\u003cp\u003e-4.260\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\n\u003cp\u003e\u0026lt;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"29%\"\u003e\n\u003cp\u003eUterine volume [cm\u003csup\u003e3\u003c/sup\u003e,\u003cem\u003e M \u003c/em\u003e(\u003cem\u003eP25-P75\u003c/em\u003e)]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003e180.17(133.82~236.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"28%\"\u003e\n\u003cp\u003e245.79(185.25~322.47)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\n\u003cp\u003e-4.453\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\n\u003cp\u003e\u0026lt;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"29%\"\u003e\n\u003cp\u003eCA125 [U/mL,\u003cem\u003e M \u003c/em\u003e(\u003cem\u003eP25-P75\u003c/em\u003e)]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003e47.88(37.20~73.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"28%\"\u003e\n\u003cp\u003e143.10(109.08~182.48)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\n\u003cp\u003e-7.885\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\n\u003cp\u003e\u0026lt;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"29%\"\u003e\n\u003cp\u003eCA19-9 [U/mL,\u003cem\u003e M \u003c/em\u003e(\u003cem\u003eP25-P75\u003c/em\u003e)]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003e20.35(17.89~31.98)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"28%\"\u003e\n\u003cp\u003e19.68(12.66~41.34)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\n\u003cp\u003e-0.223\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\n\u003cp\u003e0.823\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"29%\"\u003e\n\u003cp\u003ePT [s, \u003cem\u003eM \u003c/em\u003e(\u003cem\u003eP25-P75\u003c/em\u003e)]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003e11.10(10.45~11.65)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"28%\"\u003e\n\u003cp\u003e10.90(10.50~11.78)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\n\u003cp\u003e-0.195\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\n\u003cp\u003e0.846\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"29%\"\u003e\n\u003cp\u003ePT-INR [\u003cem\u003eM \u003c/em\u003e(\u003cem\u003eP25-P75\u003c/em\u003e)]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003e0.96(0.93~1.03)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"28%\"\u003e\n\u003cp\u003e0.96(0.93~1.01)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\n\u003cp\u003e-0.674\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\n\u003cp\u003e0.500\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"29%\"\u003e\n\u003cp\u003eAPTT [s, `\u003cem\u003ex \u0026plusmn;s\u003c/em\u003e]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003e26.54\u0026plusmn;2.43\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"28%\"\u003e\n\u003cp\u003e26.40\u0026plusmn;2.34\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\n\u003cp\u003e0.342\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\n\u003cp\u003e0.732\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"29%\"\u003e\n\u003cp\u003eFIB [g/L, \u003cem\u003eM \u003c/em\u003e(\u003cem\u003eP25-P75\u003c/em\u003e)]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003e2.48(2.25~3.19)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"28%\"\u003e\n\u003cp\u003e2.53(2.32~3.09)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\n\u003cp\u003e-0.389\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\n\u003cp\u003e0.697\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"29%\"\u003e\n\u003cp\u003eTT [s, \u003cem\u003eM \u003c/em\u003e(\u003cem\u003eP25-P75\u003c/em\u003e)]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003e17.30(16.90~17.60)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"28%\"\u003e\n\u003cp\u003e17.20(16.93~17.80)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\n\u003cp\u003e-0.060\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\n\u003cp\u003e0.953\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"29%\"\u003e\n\u003cp\u003eD-D [mg/L, \u003cem\u003eM \u003c/em\u003e(\u003cem\u003eP25-P75\u003c/em\u003e)]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003e0.21(0.15~0.34)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"28%\"\u003e\n\u003cp\u003e0.20(0.15~0.30)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\n\u003cp\u003e-1.123\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\n\u003cp\u003e0.262\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"29%\"\u003e\n\u003cp\u003eALT [U/L, \u003cem\u003eM \u003c/em\u003e(\u003cem\u003eP25-P75\u003c/em\u003e)]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003e14.40(11.65~23.95)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"28%\"\u003e\n\u003cp\u003e13.85(10.80~17.10)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\n\u003cp\u003e-1.532\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\n\u003cp\u003e0.125\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"29%\"\u003e\n\u003cp\u003eBUN [mmol/L, \u003cem\u003eM \u003c/em\u003e(\u003cem\u003eP25-P75\u003c/em\u003e)]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003e4.46(3.52~5.31)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"28%\"\u003e\n\u003cp\u003e4.40(3.50~5.80)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\n\u003cp\u003e-0.555\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\n\u003cp\u003e0.579\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"29%\"\u003e\n\u003cp\u003eCr [\u0026mu;mol/L, \u003cem\u003eM \u003c/em\u003e(\u003cem\u003eP25-P75\u003c/em\u003e)]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"19%\"\u003e\n\u003cp\u003e54.60(51.20~59.40)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"28%\"\u003e\n\u003cp\u003e54.10(52.13~60.40)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\n\u003cp\u003e-0.083\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"11%\"\u003e\n\u003cp\u003e0.934\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviation: BMI, body mass index; Hb, hemoglobin; PLT, platelet count; VAS, visual analogue pain score; CA125, carbohydrate antigen 125; CA19-9, carbohydrate antigen 19-9; PT, prothrombin time; PT-INR, international normalized ratio of prothrombin time; APTT, activated partial thromboplastin time; FIB, fibrinogen quantification; TT, thrombin time; D-D, D-dimer; ALT, alanine aminotransferase; BUN, serum urea nitrogen; Cr, creatinine. *P\u0026lt; 0.05.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n\u003ch2\u003eLoss of follow-up and discontinuation of medication\u003c/h2\u003e\n\u003cp\u003eOverall, 52/61 patients (85.2%) in the group 1 and 83/96 patients (86.5%) in the group 2 completed the 15-months follow-up. The rates of follow-up loss at this study were 6.6% (4/61) and 6.3% (6/96) in group 1 and group 2 respectively, without significant difference between groups (P\u0026thinsp;=\u0026thinsp;1.00).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n\u003ch2\u003eThe efficacy of DNG alone and GnRH-a\u0026thinsp;+\u0026thinsp;DNG treatment in adenomyosis\u003c/h2\u003e\n\u003cp\u003eThe dysmenorrhea VAS scores, Hb levels, serum CA125 and CA19-9 levels as well as uterine volume pre and post treatment in both groups were presented in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e. Both DNG alone and GnRH-a combined with DNG sequential therapy were significantly effective in controlling dysmenorrhea of adenomyosis, improveing anemia, and reduced CA125 and CA-19-9.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eThe efficacy of DNG monotherapy and GnRH-a\u0026thinsp;+\u0026thinsp;DNG sequential therapy in treating adenomyosis\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eDNG\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eitems\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eBaseline\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e3\u0026ndash;6 months\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e9\u0026ndash;12 months\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e15\u0026ndash;24 months\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eNumber of patients\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e61\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e61\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e54\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e52\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eVAS [mm, \u003cem\u003eM\u003c/em\u003e (\u003cem\u003eP25-P75\u003c/em\u003e)]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003evalue\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e70.00(70.00\u0026ndash;80.00)\u003c/p\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e00.00(00.00\u0026ndash;20.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e00.00(00.00\u0026ndash;00.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e00.00(00.00\u0026ndash;0.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT or Z-value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-9.685\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-9.353\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-9.677\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eHb [g/L, \u003cem\u003eM\u003c/em\u003e (\u003cem\u003eP25-P75\u003c/em\u003e)]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003evalue\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e120.00(99.00-136.00)\u003c/p\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e137.00(124.00-143.50)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e138.00(124.75\u0026ndash;142.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e137.00(124.00-143.50)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT or Z-value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-4.889\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-4.574\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-4.281\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eCA125 [U/mL, \u003cem\u003eM\u003c/em\u003e (\u003cem\u003eP25-P75\u003c/em\u003e)]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003evalue\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e47.88(37.20\u0026ndash;73.00)\u003c/p\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e37.00(22.75\u0026ndash;56.65)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e23.70(15.50-36.38)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20.00(12.54\u0026ndash;35.40)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT or Z-value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-2.937\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-6.381\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-6.646\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.003*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eCA19-9 [U/mL, \u003cem\u003eM\u003c/em\u003e (\u003cem\u003eP25-P75\u003c/em\u003e)]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003evalue\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e20.35(17.89\u0026ndash;31.98)\u003c/p\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16.27(10.87\u0026ndash;20.65)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13.61(8.54\u0026ndash;20.29)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15.03(6.25\u0026ndash;18.08)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT or Z-value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-3.526\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-4.626\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-5.554\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eUterine volume [cm\u003csup\u003e3\u003c/sup\u003e, \u003cem\u003eM\u003c/em\u003e (\u003cem\u003eP25-P75\u003c/em\u003e)]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003evalue\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e180.17(133.82\u0026ndash;236.00)\u003c/p\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e168.04(130.49-218.14)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e155.88(115.83-216.06)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e166.55(116.56-204.53)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT or Z-value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.494\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-1.622\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-1.550\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.621\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.105\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.121\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eGnRH-a\u0026thinsp;+\u0026thinsp;DNG\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eBaseline\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eGnRH-a 3\u0026ndash;6 injections\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e3\u0026ndash;6 months\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e9\u0026ndash;12 months\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e15\u0026ndash;24 months\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eNumber of patients\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e96\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e96\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e96\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e87\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e83\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eVAS [mm, \u003cem\u003eM\u003c/em\u003e (\u003cem\u003eP25-P75\u003c/em\u003e)]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003evalue\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e80.00(72.50\u0026ndash;80.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e00.00(00.00\u0026ndash;00.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e00.00(00.00\u0026ndash;00.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e00.00(00.00\u0026ndash;00.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e00.00(00.00\u0026ndash;00.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT or Z-value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-12.855\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-12.586\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-12.230\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-12.166\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eHb [g/L, \u003cem\u003eM\u003c/em\u003e (\u003cem\u003eP25-P75\u003c/em\u003e)]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003evalue\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e104.00(91.00-128.75)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e132.50(126.00-140.75)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e134.50(125.25-143.75)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e134.00(121.00-142.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e130.00(123.00-140.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT or Z-value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-7.345\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-7.413\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-6.656\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-5.307\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eCA125 [U/mL, \u003cem\u003eM\u003c/em\u003e (\u003cem\u003eP25-P75\u003c/em\u003e)]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003evalue\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e143.10(109.08-182.48)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e32.10(13.93\u0026ndash;71.68)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e21.50(14.33\u0026ndash;47.08)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e21.10(15.50\u0026ndash;26.90)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20.00(17.20-26.66)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT or Z-value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-9.905\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-9.898\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-10.809\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-11.067\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eCA19-9 [U/mL, \u003cem\u003eM\u003c/em\u003e (\u003cem\u003eP25-P75\u003c/em\u003e)]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003evalue\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e19.68(12.66\u0026ndash;41.34)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17.05(8.35\u0026ndash;24.59)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9.69(7.09\u0026ndash;18.32)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12.35(6.48\u0026ndash;19.10)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10.97(6.49\u0026ndash;18.61)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT or Z-value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-3.251\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-5.939\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-5.019\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-5.623\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eUterine volume [cm\u003csup\u003e3\u003c/sup\u003e, \u003cem\u003eM\u003c/em\u003e (\u003cem\u003eP25-P75\u003c/em\u003e)]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003evalue\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e245.79(185.25-322.47)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e136.25(102.62\u0026ndash;190.20)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e240.47(166.61\u0026ndash;323.40)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e242.86(165.63-305.07)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e212.94(156.45-259.39)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT or Z-value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-7.727\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.790\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-1.020\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-2.002\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.430\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.308\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.003*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"7\"\u003eAbbreviation: VAS, visual analogue pain score; Hb, hemoglobin; CA125, carbohydrate antigen 125; CA19-9, carbohydrate antigen 19\u0026thinsp;\u0026minus;\u0026thinsp;9. *Compared to pre-treatment, P\u0026thinsp;\u0026lt;\u0026thinsp;0.05. P-values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered to indicate statistical significance.\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eRegarding the change in uterine volume, no significant change was observed before and after treatment with DNG alone (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05). In group 2, uterine volume shrunk significantly after 3\u0026ndash;6 injections of GnRH-a from 245.79(185.25\u0026thinsp;~\u0026thinsp;322.47) cm\u003csup\u003e3\u003c/sup\u003e to 136.25(102.62\u0026thinsp;~\u0026thinsp;190.20) cm\u003csup\u003e3\u003c/sup\u003e (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). During the sequential treatment with DNG, the uterine volume rebound to 97.84%, 98.81%, and 86.63% of pre-treatment level at 3\u0026ndash;6, 9\u0026ndash;12 and 15\u0026ndash;24 months respectively.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n\u003ch2\u003eThe safety of DNG alone and GnRH-a\u0026thinsp;+\u0026thinsp;DNG treatment in adenomyosis\u003c/h2\u003e\n\u003cp\u003eThe coagulation function and hepatorenal function showed no significant difference in all patients in both groups (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05) (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). In terms of bleeding patterns during treatment, patients in the two groups showed variable presentations (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eThe safety of DNG monotherapy and GnRH-a\u0026thinsp;+\u0026thinsp;DNG sequential therapy in treating adenomyosis\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eDNG\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eItems\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eBaseline\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e3\u0026ndash;6 months\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e9\u0026ndash;12 months\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e15\u0026ndash;24 months\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eNumber of patients\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e61\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e61\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e54\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e52\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003ePT [s, \u003cem\u003eM\u003c/em\u003e (\u003cem\u003eP25-P75\u003c/em\u003e)]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003evalue\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e11.10(10.45\u0026ndash;11.65)\u003c/p\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11.10(10.50\u0026ndash;11.70)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11.30(10.70\u0026ndash;11.90)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11.25(10.80\u0026ndash;12.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT or Z-value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.297\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-1.935\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-1.846\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.766\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.053\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.063\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003ePT-INR [\u003cem\u003eM\u003c/em\u003e (\u003cem\u003eP25-P75\u003c/em\u003e)]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003evalue\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e0.96(0.93\u0026ndash;1.03)\u003c/p\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.00(0.95\u0026ndash;1.06)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.99(0.94\u0026ndash;1.03)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.99(0.93\u0026ndash;1.04)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT or Z-value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-1.814\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-1.013\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-1.243\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.070*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.311\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.214\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eAPTT [s, \u0026oline;\u003cem\u003ex\u0026thinsp;\u0026plusmn;\u0026thinsp;s\u003c/em\u003e]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003evalue\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e26.54\u0026thinsp;\u0026plusmn;\u0026thinsp;2.43\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e26.55\u0026thinsp;\u0026plusmn;\u0026thinsp;2.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e26.41\u0026thinsp;\u0026plusmn;\u0026thinsp;2.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e27.53\u0026thinsp;\u0026plusmn;\u0026thinsp;2.43\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT or Z-value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.021\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.269\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-1.404\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.983\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.788\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.163\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eFIB [g/L, \u003cem\u003eM\u003c/em\u003e (\u003cem\u003eP25-P75\u003c/em\u003e)]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003evalue\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e2.48(2.25\u0026ndash;3.19)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.53(2.28\u0026ndash;3.06)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.62(2.29\u0026ndash;3.09)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.59(2.26\u0026ndash;3.26)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT or Z-value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.172\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.261\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.245\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.864\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.794\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.807\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eTT [s, \u003cem\u003eM\u003c/em\u003e (\u003cem\u003eP25-P75\u003c/em\u003e)]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003evalue\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e17.30(16.90\u0026ndash;17.60)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17.00(16.30-17.65)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17.25(16.30-17.53)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17.10(16.70\u0026ndash;17.40)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT or Z-value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-1.811\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-1.433\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-1.807\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.070\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.152\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.071\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eD-D [mg/L, \u003cem\u003eM\u003c/em\u003e (\u003cem\u003eP25-P75\u003c/em\u003e)]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003evalue\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e0.21(0.15\u0026ndash;0.34)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.21(0.14\u0026ndash;0.32)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.18(0.13\u0026ndash;0.34)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.21(0.14\u0026ndash;0.32)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT or Z-value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.666\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.917\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.369\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.505\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.359\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.712\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eALT [U/L, \u003cem\u003eM\u003c/em\u003e (\u003cem\u003eP25-P75\u003c/em\u003e)]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003evalue\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e14.40(11.65\u0026ndash;23.95)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13.20(10.20\u0026ndash;17.70)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15.25(10.95\u0026ndash;22.63)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14.50(10.90\u0026ndash;19.40)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT or Z-value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-1.488\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.120\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.599\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.137\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.904\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.549\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003ePLT [*109/L, \u003cem\u003eM\u003c/em\u003e (\u003cem\u003eP25-P75\u003c/em\u003e)]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003evalue\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e238.00(217.00-279.50)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e241.00(200.50-287.50)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e241.50(203.50-284.50)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e233.00(216.50\u0026ndash;286.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT or Z-value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.187\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.734\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.063\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.852\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.463\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.949\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eBUN [mmol/L, \u003cem\u003eM\u003c/em\u003e (\u003cem\u003eP25-P75\u003c/em\u003e)]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003evalue\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e4.46(3.52\u0026ndash;5.31)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.00(3.58\u0026ndash;5.09)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.00(3.40\u0026ndash;4.95)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.30(3.50\u0026ndash;5.20)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT or Z-value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.791\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-1.071\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.105\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.429\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.284\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.916\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eCr [\u0026micro;mol/L, \u003cem\u003eM\u003c/em\u003e (\u003cem\u003eP25-P75\u003c/em\u003e)]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003evalue\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e54.60(51.20\u0026ndash;59.40)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e58.30(51.10\u0026ndash;64.90)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e54.55(52.10\u0026ndash;61.90)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e58.60(52.00-60.80)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT or Z-value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-1.931\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.423\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-1.924\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.054\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.672\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.054\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eGnRH-a\u0026thinsp;+\u0026thinsp;DNG\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eBaseline\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eGnRH-a 3\u0026ndash;6 injections\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e3\u0026ndash;6 months\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e9\u0026ndash;12 months\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e15\u0026ndash;24 months\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eNumber of patients\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e96\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e96\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e96\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e87\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e83\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003ePT [s, \u003cem\u003eM\u003c/em\u003e (\u003cem\u003eP25-P75\u003c/em\u003e)]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003evalue\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10.90(10.50-11.78)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11.20(10.45\u0026ndash;11.80)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11.00(10.60-11.68)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11.00(10.60\u0026ndash;11.50)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11.00(10.60\u0026ndash;11.50)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT or Z-value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.499\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.601\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.155\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.113\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.618\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.548\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.877\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.910\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003ePT-INR [\u003cem\u003eM\u003c/em\u003e (\u003cem\u003eP25-P75\u003c/em\u003e)]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003evalue\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.96(0.93\u0026ndash;1.01)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.96(0.90\u0026ndash;1.02)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.98(0.93\u0026ndash;1.02)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.96(0.93-1.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.96(0.92-1.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT or Z-value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.293\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-1.283\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.150\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.258\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.770\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.199\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.881\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.797\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eAPTT [s, \u0026oline;\u003cem\u003ex\u0026thinsp;\u0026plusmn;\u0026thinsp;s\u003c/em\u003e]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003evalue\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e26.40\u0026thinsp;\u0026plusmn;\u0026thinsp;2.34\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e26.37\u0026thinsp;\u0026plusmn;\u0026thinsp;2.36\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e26.31\u0026thinsp;\u0026plusmn;\u0026thinsp;2.18\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e26.56\u0026thinsp;\u0026plusmn;\u0026thinsp;2.86\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e26.40\u0026thinsp;\u0026plusmn;\u0026thinsp;2.34\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT or Z-value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.106\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.292\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.417\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-1.292\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.916\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.771\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.677\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.198\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eFIB [g/L, \u003cem\u003eM\u003c/em\u003e (\u003cem\u003eP25-P75\u003c/em\u003e)]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003evalue\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.53(2.32\u0026ndash;3.09)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.59(2.24\u0026ndash;2.85)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.68(2.41-3.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.57(2.33\u0026ndash;2.83)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.47(2.08\u0026ndash;2.82)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT or Z-value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.479\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-1.423\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.366\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-1.921\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.632\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.155\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.714\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.055\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eTT [s, \u003cem\u003eM\u003c/em\u003e (\u003cem\u003eP25-P75\u003c/em\u003e)]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003evalue\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17.20(16.93\u0026ndash;17.80)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17.30(16.93\u0026ndash;17.78)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17.15(16.63\u0026ndash;17.70)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17.10(16.80\u0026ndash;17.70)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17.10(16.80\u0026ndash;17.60)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT or Z-value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.212\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-1.536\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-1.402\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-1.926\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.832\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.125\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.161\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.054\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eD-D [mg/L, \u003cem\u003eM\u003c/em\u003e (\u003cem\u003eP25-P75\u003c/em\u003e)]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003evalue\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.20(0.15\u0026ndash;0.30)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.21(0.15\u0026ndash;0.31)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.19(0.14\u0026ndash;0.27)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.21(0.14\u0026ndash;0.29)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.18(0.13\u0026ndash;0.33)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT or Z-value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.919\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.620\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.547\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.003\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.358\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.535\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.585\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.998\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eALT [U/L, \u003cem\u003eM\u003c/em\u003e (\u003cem\u003eP25-P75\u003c/em\u003e)]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003evalue\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13.85(10.80\u0026ndash;17.10)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12.95(10.50-17.38)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13.75(10.55\u0026ndash;18.60)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14.30(11.40\u0026ndash;19.10)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14.20(10.60\u0026ndash;20.60)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT or Z-value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.084\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.542\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-1.585\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-1.141\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.933\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.588\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.113\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.254\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003ePLT [*109/L, \u003cem\u003eM\u003c/em\u003e (\u003cem\u003eP25-P75\u003c/em\u003e)]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003evalue\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e256.00(214.25\u0026ndash;291.50)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e246.00(210.00-290.50)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e236.50(215.50-280.50)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e246.00(200.00-281.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e244.00(214.00-285.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT or Z-value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.594\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-1.218\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-1.480\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.683\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.553\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.223\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.139\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.495\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eBUN [mmol/L, \u003cem\u003eM\u003c/em\u003e (\u003cem\u003eP25-P75\u003c/em\u003e)]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003evalue\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.40(3.50\u0026ndash;5.80)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.50(3.60\u0026ndash;5.57)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.40(3.53\u0026ndash;5.29)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.50(3.60\u0026ndash;5.50)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.66(3.70\u0026ndash;5.70)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT or Z-value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.256\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.287\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.020\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.710\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.798\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.774\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.984\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.478\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eCr [\u0026micro;mol/L, \u003cem\u003eM\u003c/em\u003e (\u003cem\u003eP25-P75\u003c/em\u003e)]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003evalue\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e54.10(52.13\u0026ndash;60.40)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e53.25(49.50\u0026ndash;58.60)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e53.85(48.95\u0026ndash;60.60)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e54.30(49.20\u0026ndash;59.30)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e53.90(50.30\u0026ndash;58.30)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT or Z-value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-1.667\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-1.086\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-1.083\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-1.027\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.096\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.278\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.279\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.304\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"7\"\u003eAbbreviation: PT, prothrombin time; PT-INR, international normalized ratio of prothrombin time; APTT, activated partial thromboplastin time; FIB, fibrinogen quantification; TT, thrombin time; D-D, D-dimer; ALT, alanine aminotransferase; BUN, serum urea nitrogen; Cr, creatinine.\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"7\"\u003e* Compared to pre-treatment, P\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe amenorrhea rates in group1 at 1\u0026ndash;3 months, 4\u0026ndash;6 months and \u0026gt;\u0026thinsp;6 months were 40.98% (25/61), 66.67% (38/57) and 77.78% (42/54) respectively. The incidence of irregular spotting bleeding was 52.46% (32/61), 33.33% (19/57) and 22.22% (12/54), respectively. It is noteworthy that four patients (4/61,6.56%) experienced a heavy breakthrough bleeding during 1\u0026ndash;3 months of DNG alone. For two of these patients, the DNG dose was increased to 3\u0026ndash;4 mg/day for 7 days and then continued at 2 mg/day maintenance without unpredictable breakthrough bleeding during the next maintenance therapy. However, two other patients had poor efficacy after 7 days of treatment with 4 mg/day, which led them to switch to GnRH-a 3\u0026ndash;6 injections followed by a DNG maintenance regimen. In group 2, at the 1\u0026ndash;3 months, 4\u0026ndash;6 months and \u0026gt;\u0026thinsp;6 months of sequential DNG treatment, the amenorrhea rate was 68.75% (66/96), 66.30% (61/92) and 70.45% (62/88) respectively. The incidence of irregular spotting bleeding was 31.25% (30/96), 33.70% (31/92) and 26.14% (23/88) respectively. Three patients (3/88,3.41%) experienced breakthrough bleeding at 6 ,6 and 24 months of sequential DNG treatment respectively. Two of the three patients were restarted with GnRH-a 3\u0026ndash;6 injections followed by DNG treatment. Another patient underwent diagnostic curettage for thickened endometrium and postoperative pathology revealed a secretory stage endometrium. Unfortunately, this patient was subsequently lost to follow-up.\u003c/p\u003e\n\u003cp\u003eWhether treated with DNG alone or GnRH-a combined with DNG sequentially, we did not observe any significant abnormal lesions in the patients' breast tissue during the follow-up period (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e), but a few patients showed variation in the size and location of their breast nodules. After consultation with the breast specialist, all of these patients had no indication for surgery and were advised to have the breast ultrasound every 3 months while taking DNG.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Tab3\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eThe impact of DNG monotherapy and GnRH-a\u0026thinsp;+\u0026thinsp;DNG sequential therapy on breast tissue\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth colspan=\"4\" align=\"left\"\u003e\n\u003cp\u003eDNG\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"4\" align=\"left\"\u003e\n\u003cp\u003eGnRH-a\u0026thinsp;+\u0026thinsp;DNG\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ePre-treatment\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e3\u0026ndash;6 months\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e9\u0026ndash;12 months\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e15\u0026ndash;24 months\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ePre-treatment\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e3\u0026ndash;6 months\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e9\u0026ndash;12 months\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e15\u0026ndash;24 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align=\"left\"\u003e\n\u003cp\u003eUnilateral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBI-RADS 1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBI-RADS 2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBI-RADS 3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9(-1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8(-1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eBilateral\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBI-RADS 1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBI-RADS 2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2(-1)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBI-RADS 3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11(+\u0026thinsp;1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12(+\u0026thinsp;1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14(+\u0026thinsp;2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17(+\u0026thinsp;2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18(+\u0026thinsp;1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e19(+\u0026thinsp;1)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eTotal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e57\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e86\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":" \u003cp\u003e \u003cb\u003e1. The efficacy of DNG alone and GnRH-a\u0026thinsp;+\u0026thinsp;DNG on dysmenorrhea.\u003c/b\u003e \u003c/p\u003e \u003cp\u003eMany studies have demonstrated the benefit of DNG in relieving the dysmenorrhea symptoms of adenomyosis \u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan additionalcitationids=\"CR13 CR14\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. To the long-term efficacy of DNG on adenomyosis, Osuga Y et al reported that the mean VAS values decreased 56.7\u0026thinsp;\u0026plusmn;\u0026thinsp;24.2 mm at 52 weeks of DNG treatment \u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e. Neriishi K et al even noted that DNG has a remarkable pain relief effect continued up to menopause or for a long period of \u0026gt;\u0026thinsp;80 months \u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. Matsushima T et al reported that after 6 months of GnRH-a or DNG, all patients\u0026rsquo; subjective symptoms disappeared. But symptoms recurred rapidly in the first six months after discontinuation of GnRH-a treatment \u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e. In our study, patients exhibited a higher complete relief of dysmenorrhea after 3\u0026ndash;6 injections of GnRH-a than 3\u0026ndash;6 months of DNG alone. From 9\u0026ndash;12 months, the complete pain relief rate was comparable in both groups. This suggests that long-term (\u0026ge;\u0026thinsp;12 months) treatment with DNG alone or sequential treatment with DNG after GnRH-a is comparable in controlling adenomyosis-related dysmenorrhea.\u003c/p\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eThe effect of DNG alone and GnRH-a\u0026thinsp;+\u0026thinsp;DNG on serum CA125 and CA19-9\u003c/h2\u003e \u003cp\u003eItagaki H et al found that the serum CA125 level correlated positively with the weight of adenomyosis and it is an important indicator for evaluating recurrence \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e7]\u003c/sup\u003e. Kil K et al. even proposed that the cut-off value of 19 U/mL for serum CA125 provides a better differentiation between adenomyosis and myomas \u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e. In studies assessing the efficacy of DNG on symptomatic adenomyosis, serum CA125 was also an important evaluator. Hirata T et al found that the serum CA125 significantly decreased from 150.6\u0026thinsp;\u0026plusmn;\u0026thinsp;136.4 U/mL (baseline) to 69.5\u0026thinsp;\u0026plusmn;\u0026thinsp;88.4 U/mL at 24 weeks of DNG treatment \u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e. Neriishi K et al. observed a significant decrease in serum CA125 from 124.1\u0026thinsp;\u0026plusmn;\u0026thinsp;84.0 to 19.6\u0026thinsp;\u0026plusmn;\u0026thinsp;6.7 IU/ml with long-term DNG administration (\u0026gt;\u0026thinsp;80 months) \u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. Matsushima T et al noted that after 16 weeks of treatment, the effect of DNG in lowering serum CA125 can be comparable to that of GnRH-a and lowdose estrogenprogestin combination \u003csup\u003e[19]\u003c/sup\u003e. In our study, CA125 levels decreased by 22.72%, 50.50% and 58.23% after 3\u0026ndash;6, 9\u0026ndash;12 and 15\u0026ndash;24 months of treatment with DNG alone, respectively. In group 2, CA125 levels dropped by 77.62% after 3\u0026ndash;6 injections of GnRH-a. After 3\u0026ndash;6, 9\u0026ndash;12, and 15\u0026ndash;24 months of subsequent maintenance treatment with DNG, CA125 levels declined by 85.07%, 85.29%, and 86.02%, respectively. This suggests that GnRH-a\u0026thinsp;+\u0026thinsp;DNG sequencing therapy is superior to DNG monotherapy in lowering CA125 levels.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eThe effect of DNG alone and GnRH-a\u0026thinsp;+\u0026thinsp;DNG on uterine volume\u003c/h2\u003e \u003cp\u003eRegarding the effect of DNG on uterine volume of adenomyosis, the current studies were inconsistent. Fawzy et al. observed that uterine volume decreased by 12.27% (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05) after 16 weeks of treatment with DNG \u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e. Hirata et al. showed that uterine volume decreased by 8.97% (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05) in patients treated with DNG for 6 months \u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e. Osuga Y et al. found that the mean reduction in uterine size was 20.6\u0026thinsp;\u0026plusmn;\u0026thinsp;30.3% at 24 weeks and 26.0\u0026thinsp;\u0026plusmn;\u0026thinsp;27.9% at 52 weeks of DNG treatment \u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e. Neriishi K et al. discovered that long-term DNG administration (\u0026gt;\u0026thinsp;80 months) resulted in a significant 30.49% reduction (P\u0026thinsp;\u0026lt;\u0026thinsp;0.01) in uterine size \u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. Hassanin AI et al observed that uterine volume decreased 31.57% (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05) and 8.02% (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05) respectively when treated with DNG and COCs for 6 months \u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. Similar decreases were observed in the diffuse and focal subtypes of adenomyosis treated with DNG at 12 to 24 months \u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e. Nevertheless, Ji et al. found that uterine volume increased by 15.33% (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05) after 12 weeks of treatment with DNG \u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e. Matsushima T et al reported that after treated with DNG for 16 weeks, the uterine volume increased 12.68% \u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e. Their team also noticed that the uterine volume decreased by 54.25% after 6 injections with GnRH-a and rebounded to 82.79% of the pre-treatment volume after 6 months of discontinuation. When DNG was supplemented for 6 months after discontinuing GnRH-a, the uterine volume was 72.24% of the pre-treatment level \u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e. In our study, when treated with DNG alone, the uterine volume decreased 6.73%, 13.48% and 7.56% at 3\u0026ndash;6, 9\u0026ndash;12 and 15\u0026ndash;24 months respectively (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05). In group 2, uterine volume shrunk 44.57% (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05) after 3\u0026ndash;6 injections GnRH-a and then rebound to 97.84%, 98.81%, and 86.63% of pre-treatment level at 3\u0026ndash;6, 9\u0026ndash;12 and 15\u0026ndash;24 months of sequential DNG treatment. At the endpoint of this study (15\u0026ndash;24 months), GnRH-a combined with DNG sequential therapy was superior to DNG monotherapy in reducing uterine volume.\u003c/p\u003e \u003cp\u003e \u003cb\u003eThe effect of DNG alone and GnRH-a\u0026thinsp;+\u0026thinsp;DNG on hemoglobin and uterine bleeding pattern.\u003c/b\u003e \u003c/p\u003e \u003cp\u003eMenorrhagia and anemia are the common clinical manifestations in patients with adenomyosis. It has been observed that the Hb increased from 11.6\u0026thinsp;\u0026plusmn;\u0026thinsp;1.5 mg/dL to 12.3\u0026thinsp;\u0026plusmn;\u0026thinsp;2.0 mg/dL at 24 weeks of DNG treatment \u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e. Osuga Y et al. reported that DNG treatment caused an improvement of Hb from 12.8\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2 g/dL to 13.5\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9 g/dL (24 weeks) and 13.5\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9 g/dL (52 weeks) \u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e. Matsushima T et al found that the elevated levels of Hb were comparable between patients treated with GnRH-a and DNG for 6 months. \u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e. Hassanin et al. also observed that the improvement of Hb in patients taking DNG for 6 months was comparable to that of patients taking COC for 6 months \u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. Our study also showed that either DNG alone or GnRH-a followed by DNG significantly increased Hb levels and improved anemia symptoms. (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e \u003cp\u003eIrregular uterine bleeding is a common symptom experienced by women treated with DNG, especially in the first 3 months of treatment. Fortunately, as treatment continues, the length and intensity of uterine bleeding decreases \u003csup\u003e[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e. Uterine bleeding induced by DNG was more likely to occur in subjects with adenomyosis than in those with endometriosis alone \u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e. In endometriosis, the number of discontinuations due to heavy or irregular bleeding was low (2/332) \u003csup\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e. However, in adenomyosis, the number of these patients increased greatly. Nagata C et al. reported that 36 of 51 patients (70.6%) continued DNG treatment for more than 12 months, and 8 (15.7%) patients discontinued treatment due to uterine bleeding. High risk factors for discontinuation of DNG treatment included age\u0026thinsp;\u0026lt;\u0026thinsp;38 years, Hb\u0026thinsp;\u0026lt;\u0026thinsp;12 g/L prior to treatment, and estradiol\u0026thinsp;\u0026ge;\u0026thinsp;60 pg/ml at the third month of treatment \u003csup\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e. Matsubara S et al. found that 14 of 37 patients (37.8%) with symptomatic adenomyosis experienced severe unpredictable bleeding during DNG treatment that was associated with subtype I (intrinsic) adenomyosis \u003csup\u003e[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e. Neriishi K et al. discovered that 22.2% (4/18) of patients stopped DNG therapy because of severe metrorrhagia and the mean duration of DNG treatment was 7.0\u0026thinsp;\u0026plusmn;\u0026thinsp;3.5 months. Compared with patients taking DNG continuously, the dysmenorrhea VAS score and serum CA125 level at baseline were significantly increased and the basal Hb level and the frequency of subtype II (extrinsic) were significantly decreased in the cases of discontinuation \u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. Ono N et al observed that 35% (7/20) of women discontinued DNG within 12 months due to unbearable metrorrhagia. The uterus size was significantly larger and anterior wall lesions were more common in the discontinued group than in the continued group. They proposed that patients with uterine major axis of less than 9 cm, minor axis of 6 cm, maximum myometrial thickness of 4cm, and uterine body length of 4.5cm could tolerate DNG treatment \u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e. In our study, pretreatment with GnRH-a achieved better amenorrhea rates and lower spotting bleeding rate.\u003c/p\u003e \u003cp\u003eHowever, both groups had cases of heavy breakthrough bleeding during treatment, that is, four patients (4/61,6.56%) in group 1 and three cases (3/88,3.41%) in group 2. The clinical characteristics of these patients were analyzed retrospectively. 6 patients (6/7, 85.71%) had diffuse adenomyosis lesions, 5 patients (5/7, 71.43%) showed lesions compressing the endometrium, and 5 patients (5/7, 71.43%) had hemoglobin\u0026thinsp;\u0026lt;\u0026thinsp;105 g/L before treatment. Regarding the CA125 level, three patients (3/4,75.00%) treated with group 1 and two patients (2/3, 66.67%) in group 2 were above the average level within the group.\u003c/p\u003e \u003cp\u003eAs to the management of unpredictable bleeding during DNG treatment, a 5\u0026thinsp;~\u0026thinsp;7-day break of DNG, DNG dose increased from 2 mg to 4 mg daily for 5\u0026ndash;7 days or a short-term application of 1 mg estradiol have been described as valid approaches to interrupt the uterine bleeding \u003csup\u003e[\u003cspan additionalcitationids=\"CR28\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/sup\u003e. Another option was to treat with GnRH-a to achieve amenorrhea and then switch to DNG \u003csup\u003e[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/sup\u003e. In this study, two patients in the group 1 increased to 3\u0026ndash;4 mg/day for 7 days and then continued at 2 mg/day maintenance without unpredictable breakthrough bleeding during the next follow-up. Another two patients in group 1 were switched to GnRH-a injection followed by DNG because of poor efficacy after double-dose treatment with DNG. Two patients in group 2 were re-injected with GnRH-a followed by DNG.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eThe safety of DNG\u003c/h2\u003e \u003cp\u003eOverall, DNG was a well-tolerated treatment for symptomatic adenomyosis with a good safety for long-term use. It had no adverse effects on hepatorenal and coagulation function during the treatment. As to the effect of DNG on breast, four randomized clinical trials of 2 mg DNG treatment in 332 women with endometriosis, 18 (5.4%) women reported breast discomfort, including 11 cases of breast tenderness, 4 cases of breast swelling, and 3 cases of breast pain \u003csup\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e. In this study, A few patients showed variations in the size and location of breast nodules. But none of the breast nodules progressed to BI-RADS 4 lesions. More cases and longer time are required to further evaluate the effect of DNG on breast.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOverall, our study confirmed the efficacy and good tolerability of long-term DNG use in symptomatic adenomyosis. GnRH-a combined with DNG sequential therapy was superior to DNG monotherapy in reducing uterine volume, lowering CA125 level, achieving higher amenorrhea rate and lower spotting bleeding rate. Diffuse lesions, and lesion involvement of the endometrium were the high-risk factors of heavy breakthrough bleeding during DNG treatment. The effect of DNG on the breast needs more cases and more time to be further evaluated. However, as a single-center retrospective study, this study inevitably had many limitations. For example, the subjective bias of clinicians in the selection of treatment regimens and the different adenomyosis characteristics at baseline of the two groups. Multicenter, randomized and double-blind prospective are needed to further clarify the efficacy and safety of DNG monotherapy and GnRH-a combined with DNG sequencing therapy on symptomatic adenomyosis.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eXiuli Wang: study conception and design, data validation, data analysis and manuscript revision.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eShu Zhu: data review, statistics and analysis, manuscript writing.\u003c/p\u003e\n\u003cp\u003eQiqin Wang: Data collections, statistics and analysis.\u003c/p\u003e\n\u003cp\u003eJiafan Sun: patient follow-up, data collection\u003c/p\u003e\n\u003cp\u003eWei Xu: data review, statistics and analysis, partial manuscript writing.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHuiyuan Zhang: patient follow-up, data collection.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eXianglian Wang: data statistical analysis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWennian Yu: patient follow-up, data collection.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that no funds, grants, or other support were received during the preparation of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no conflicts of interest to declare that are relevant to the content of this article.\u003cbr\u003e\u003cstrong\u003eEthical approval\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by the Medical Ethics Committee of Jiangsu Province Hospital (2023-SR-070).\u003cbr\u003e\u0026nbsp;Informed consent Written informed consents were obtained from all participants before the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed consent\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformed consent was obtained from all individual\u0026nbsp;participants included in the study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBourdon M, Santulli P, Marcellin L, Maignien C, Maitrot-Mantelet L, Bordonne C (2021) Adenomyosis: An update regarding its diagnosis and clinical features. Gynecol Obstet Hum Reprod 50:102228. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.jogoh.2021.102228\u003c/span\u003e\u003cspan address=\"10.1016/j.jogoh.2021.102228\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchrager S, Yogendran L, Marquez CM, Sadowski EA (2022) Adenomyosis: Diagnosis and Management. Am Fam Physician 105(1):33\u0026ndash;38\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFerrero S, Remorgida V, Venturini PL, Bizzarri N (2015) Endometriosis: the effffects of dienogest. BMJ Clin Evid 2015:0802\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHassanin AI, Youssef AA, Yousef AM, Ali MK (2021) Comparison of dienogest versus combined oral contraceptive pills in the treatment of women with adenomyosis: A randomized clinical trial. Int J Gynaecol Obstet 154:263\u0026ndash;269. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1002/ijgo.13600\u003c/span\u003e\u003cspan address=\"10.1002/ijgo.13600\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKhialani D, Rosendaal F, Vlieg AVH (2020) Hormonal Contraceptives and the Risk of Venous Thrombosis. Semin Thromb Hemost 46:865\u0026ndash;871. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1055/s-0040-1715793\u003c/span\u003e\u003cspan address=\"10.1055/s-0040-1715793\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYoum J, Lee HJ, Kim SK, Kim H, Jee BC (2014) Factors affecting the spontaneous expulsion of the levonorgestrel-releasing intrauterine system. Int J Gynaecol Obstet 126:165\u0026ndash;169. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.ijgo.2014.02.017\u003c/span\u003e\u003cspan address=\"10.1016/j.ijgo.2014.02.017\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOta I, Taniguchi F, Ota Y, Nagata H, Wada I, Nakaso T (2021) A controlled clinical trial comparing potent progestins, LNG-IUS and dienogest, for the treatment of women with adenomyosis. Reprod Med Biol 20:427\u0026ndash;434. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1002/rmb2.12408\u003c/span\u003e\u003cspan address=\"10.1002/rmb2.12408\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang S, Liu Y, Wen J, Sun Y, Ren F (2022) Clinical Efficacy of Dienogest versus Levonorgestrel-Releasing Intrauterine System for Adenomyosis. Evid Based Complement Alternat Med 2022:1995472. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1155/2022/1995472\u003c/span\u003e\u003cspan address=\"10.1155/2022/1995472\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJi M, Yuan M, Jiao X, Li Q, Huang Y, Li J (2022) A cohort study of the efficacy of the dienogest and the gonadotropin-releasing hormone agonist in women with adenomyosis and dysmenorrhea. Gynecol Endocrinol 38:164\u0026ndash;169. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1080/09513590.2021.2000961\u003c/span\u003e\u003cspan address=\"10.1080/09513590.2021.2000961\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChapron C, Vannuccini S, Santulli P, Abr\u0026atilde;o MS, Carmona F, Fraser IS (2020) Diagnosing adenomyosis: an integrated clinical and imaging approach. Hum Reprod Update 26:392\u0026ndash;411. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1093/humupd/dmz049\u003c/span\u003e\u003cspan address=\"10.1093/humupd/dmz049\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSpak DA, Plaxco JS, Santiago L, Dryden MJ, Dogan BE (2017) BI-RADS\u0026reg; fifth edition: A summary of changes. Diagn Interv Imaging 98:179\u0026ndash;190. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.diii.2017.01.001\u003c/span\u003e\u003cspan address=\"10.1016/j.diii.2017.01.001\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOsuga Y, Fujimoto Okabe H, Hagino A (2017) Evaluation of the efficacy and safety of dienogest in the treatment of painful symptoms in patients with adenomyosis: a randomized, double blind, multicenter, placebo controlled study. Fertil Steril 108:673678. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.fertnstert.2017.07.021\u003c/span\u003e\u003cspan address=\"10.1016/j.fertnstert.2017.07.021\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHirata T, Izumi G, Takamura M, Saito A, Nakazawa A, Harada M, Hirota Y, Koga K, Fujii T, Osuga Y (2014) Efficacy of dienogest in the treatment of symptomatic adenomyosis: a pilot study. Gynecol Endocrinol 30:726\u0026ndash;729. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3109/09513590.2014.926882\u003c/span\u003e\u003cspan address=\"10.3109/09513590.2014.926882\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOsuga Y, Watanabe M, Hagino A (2017) Long term use of dienogest in the treatment of painful symptoms in adenomyosis. J Obstet Gynaecol Res 43:14411448. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1111/jog.13406\u003c/span\u003e\u003cspan address=\"10.1111/jog.13406\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNeriishi K, Hirata T, Fukuda S, Izumi G, Nakazawa A, Yamamoto N (2018) Long-term dienogest administration in patients with symptomatic adenomyosis. J Obstet Gynaecol Res 44:1439\u0026ndash;1444. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1111/jog.13674\u003c/span\u003e\u003cspan address=\"10.1111/jog.13674\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMatsushima T, Akira S, Yoneyama K, Takeshita T (2020) Recurrence of uterine adenomyosis after administration of gonadotropin-releasing hormone agonist and the efficacy of dienogest. Gynecol Endocrinol 36:521\u0026ndash;524. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1080/09513590.2019.1683818\u003c/span\u003e\u003cspan address=\"10.1080/09513590.2019.1683818\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eItagaki H, Nishida M, Kodaira Y, Sakanaka M, Ichikawa R, Arai Y (2022) Relationship between the serum cancer antigen 125 level and the weight of surgically enucleated adenomyosis. J Obstet Gynaecol 42(6):2064\u0026ndash;2068. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1080/01443615.2022.2065906\u003c/span\u003e\u003cspan address=\"10.1080/01443615.2022.2065906\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKil K, Chung JE, Pak HJ, Jeung IC, Kim JH, Jo HH (2015) Usefulness of CA125 in the differential diagnosis of uterine adenomyosis and myoma. Eur J Obstet Gynecol Reprod Biol 185:131\u0026ndash;135. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.ejogrb.2014.12.008\u003c/span\u003e\u003cspan address=\"10.1016/j.ejogrb.2014.12.008\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMatsushima T, Akira S, Fukami T, Yoneyama K, Takeshita T (2018) Efficacy of Hormonal Therapies for Decreasing Uterine Volume in Patients with Adenomyosis. Gynecol Minim Invasive Ther 7:119\u0026ndash;123. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.4103/GMIT.GMIT_35_18\u003c/span\u003e\u003cspan address=\"10.4103/GMIT.GMIT_35_18\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFawzy M, Mesbah Y (2015) Comparison of dienogest versus triptorelin acetate in premenopausal women with adenomyosis: a prospective clinical trial. Arch Gynecol Obstet 292:1267\u0026ndash;1271. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s00404-015-3755-5\u003c/span\u003e\u003cspan address=\"10.1007/s00404-015-3755-5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang S, Liu Y, Wen J, Sun Y, Ren F (2022) Clinical Efficacy of Dienogest versus Levonorgestrel-Releasing Intrauterine System for Adenomyosis. Evid Based Complement Alternat Med 2022:1995472. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1155/2022/1995472\u003c/span\u003e\u003cspan address=\"10.1155/2022/1995472\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOsuga Y, Hayashi K, Kanda S (2020) Long-term use of dienogest for the treatment of primary and secondary dysmenorrhea. J Obstet Gynaecol Res 46:606\u0026ndash;617. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1111/jog.14209\u003c/span\u003e\u003cspan address=\"10.1111/jog.14209\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStrowitzki T, Faustmann T, Gerlinger C, Schumacher U, Ahlers C, Seitz C (2015) Safety and tolerability of dienogest in endometriosis: pooled analysis from the European clinical study program. Int J Womens Health 7:393\u0026ndash;401. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.2147/IJWH.S77202\u003c/span\u003e\u003cspan address=\"10.2147/IJWH.S77202\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNagata C, Yanagida S, Okamoto A, Morikawa A, Sugimoto K, Okamoto S (2012) Risk factors of treatment discontinuation due to uterine bleeding in adenomyosis patients treated with dienogest. J Obstet Gynaecol Res 38:639\u0026ndash;644. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1111/j.1447-0756.2011.01778.x\u003c/span\u003e\u003cspan address=\"10.1111/j.1447-0756.2011.01778.x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMatsubara S, Kawaguchi R, Akinishi M, Nagayasu M, Iwai K, Niiro E (2019) Subtype I (intrinsic) adenomyosis is an independent risk factor for dienogest-related serious unpredictable bleeding in patients with symptomatic adenomyosis. Sci Rep 9:17654. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1038/s41598-019-54096-z\u003c/span\u003e\u003cspan address=\"10.1038/s41598-019-54096-z\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOno N, Asano R, Nagai K, Sugo Y, Nakamura T, Miyagi E (2021) Evaluating the safety of dienogest in women with adenomyosis: A retrospective analysis. J Obstet Gynaecol Res 47:1433\u0026ndash;1440. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1111/jog.14612\u003c/span\u003e\u003cspan address=\"10.1111/jog.14612\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eR\u0026ouml;mer T (2018) Long-term treatment of endometriosis with dienogest: retrospective analysis of efficacy and safety in clinical practice. Arch Gynecol Obstet 298:747\u0026ndash;753. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s00404-018-4864-8\u003c/span\u003e\u003cspan address=\"10.1007/s00404-018-4864-8\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNirgianakis K, Vaineau C, Agliati L, McKinnon B, Gasparri ML, Mueller MD (2021) Risk factors for non-response and discontinuation of Dienogest in endometriosis patients: A cohort study. Acta Obstet Gynecol Scand 100:30\u0026ndash;40. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1111/aogs.13969\u003c/span\u003e\u003cspan address=\"10.1111/aogs.13969\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMurji A, Biberoğlu K, Leng J, Mueller MD, R\u0026ouml;mer T, Vignali M (2020) Use of dienogest in endometriosis: a narrative literature review and expert commentary. Curr Med Res Opin 36:895\u0026ndash;907. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1111/aogs.13969\u003c/span\u003e\u003cspan address=\"10.1111/aogs.13969\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKitawaki J, Kusuki I, Yamanaka K, Suganuma I (2011) Maintenance therapy with dienogest following gonadotropin-releasing hormone agonist treatment for endometriosis-associated pelvic pain. Eur J Obstet Gynecol Reprod Biol 157:212\u0026ndash;216. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.ejogrb.2011.03.012\u003c/span\u003e\u003cspan address=\"10.1016/j.ejogrb.2011.03.012\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Adenomyosis, dienogest, GnRH-a, dysmenorrhea.","lastPublishedDoi":"10.21203/rs.3.rs-3509174/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3509174/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eTo investigate the efficacy and safety of dienogest((DNG) monotherapy and gonadotropin-releasing hormone agonist (GnRH-a) combined with DNG sequential treatment for adenomyosis.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis is a retrospective study.157 patients with symptomatic adenomyosis from the first affiliated hospital of Nanjing Medical University were enrolled in the study. 61patients treated with DNG (2mg/day) alone(Group 1). 96 patients treated with DNG (2mg/day) after 3\u0026ndash;6 injections of GnRH-a(Group 2).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003e \u003cem\u003e(\u003c/em\u003e1) The Visual analogue scale (VAS) for dysmenorrhea, serum carbohydrate antigen (CA-125) and CA19-9 levels significantly decreased in both groups compared with pre-treatment (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). (2) The hemoglobin (Hb) level in both groups after treatment were significantly higher than pre-treatment (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). (3) At 15\u0026ndash;24 months of DNG treatment, uterine volume decreased significantly in Group2 compared to pre-treatment (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05), with no significant change in Group1. (4) Group 2 showed a higher rate of amenorrhea and a lower incidence of irregular spotting and breakthrough bleeding. (5) There were no significant changes in coagulation, hepatorenal function and breast tissue before and after treatment in both groups.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eBoth DNG monotherapy and GnRH-a\u0026thinsp;+\u0026thinsp;DNG sequential therapy significantly relieved dysmenorrhea, improved anemia, and reduced CA125 and CA19-9 levels in patients with symptomatic adenomyosis, with no adverse effects on coagulation, hepatorenal function and breast tissue. The sequential therapy is superior to DNG monotherapy in reducing uterine volume and lowering CA125 levels. Sequential therapy achieved better amenorrhea rate. Diffuse lesions and lesion involvement of the endometrium were the high-risk factors of heavy breakthrough bleeding during DNG treatment.\u003c/p\u003e","manuscriptTitle":"Efficacy and safety of dienogest versus GnRH-a combined with dienogest therapy for adenomyosis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-11-29 16:25:41","doi":"10.21203/rs.3.rs-3509174/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"773e0118-c3d3-4aa9-9345-7a6d4295a3d1","owner":[],"postedDate":"November 29th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-01-15T03:11:36+00:00","versionOfRecord":[],"versionCreatedAt":"2023-11-29 16:25:41","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3509174","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3509174","identity":"rs-3509174","version":["v1"]},"buildId":"k6vKHA0u1VdKjwwnw531e","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}